Amine derivatives as potassium channel blockers

ABSTRACT

The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application under 35 U.S.C. § 371of International application number PCT/AU2012/000538, filed May 16,2012, which claims priority to U.S. provisional application Ser. No.61/486,536, filed on May 16, 2011, the entirety of each of which ishereby incorporated by reference.

FIELD OF INVENTION

The present invention relates to compounds useful in the modulation ofpotassium channel activity in cells, in particular the activity of Kv1.3channels found in T cells. The invention also relates to the use ofthese compounds in the treatment or prevention of autoimmune andinflammatory diseases, including multiple sclerosis, pharmaceuticalcompositions containing these compounds and methods for theirpreparation.

BACKGROUND

Potassium channels represent a complex class of voltage-gated ionchannels from both functional and structural standpoints. Theirfunctions include regulating neurotransmitter release, heart rate,insulin secretion, neuronal excitability, epithelial electrolytetransport, smooth muscle contraction, and cell volume. In general, foursequence-related potassium channel genes—shaker, shaw, shab, andshal—have been identified in Drosophila, and each has been shown to havehuman homolog(s). KCNA3 encodes the voltage-gated K_(V)1.3 potassiumchannel, which is shaker-related and is expressed in lymphocytes (T andB lymphocytes), the central nervous system, fat and other tissues. Thefunctional channel is composed of four identical K_(V)1.3 α-sub units.The K_(V)1.3 potassium channel regulates membrane potential and therebyindirectly influences calcium signaling in human effector-memory T cells(Grissmer S. et al, Proc. Natl. Acad. Sci. U.S.A. 87(23): 9411-5;DeCoursey T. E. et al, Nature 307 (5950): 465-8; Chandy K. G. et al,Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin. Invest.111 (11): 1703-13). Effector memory T cells are important mediators ofmultiple sclerosis, Type I diabetes mellitus, psoriasis, and rheumatoidarthritis.

The K_(v)1.3 channel is expressed in T and B lymphocytes in a distinctpattern that depends on the state of lymphocyte activation anddifferentiation. Upon activation, naive and central memory T cellsincrease expression of the KCa3.1 channel per cell, whileeffector-memory T cells increase expression of the K_(V)1.3 channel.Amongst human B cells, naive and early memory B cells express smallnumbers of K_(V)1.3 and KCa3.1 channels when they are quiescent, andaugment KCa3.1 expression after activation. In contrast, class-switchedmemory B cells express high numbers of K_(V)1.3 channels per cell (about1500/cell) and this number increases after activation (Chandy K. G. etal, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. et al, J. Clin.Invest. I I I (11): 1703-13; Wulff H. et al, J. Immunol. 173(2):776-86). The K_(v) 1.3 channel promotes the calcium homeostasis requiredfor T-cell receptor-mediated cell activation, gene transcription, andproliferation (Panyi, G et al (2004) Trends Immunol 25:565-569). Kv1.3is physically coupled through a series of adaptor proteins to the T-cellreceptor signaling complex and it traffics to the immunological synapseduring antigen presentation. However, blockade of the channel does notprevent immune synapse formation (Panyi G. et al, Proc. Natl. Acad. Sci.U.S.A., 101(5):1285-90; Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A.,103(46): 17414-9). K_(V)1.3 and KCa3.1 regulate membrane potential andcalcium signaling of T cells. Calcium entry through the CRAC channel ispromoted by potassium efflux through the K_(V)1.3 and KCa3.1 potassiumchannels. Blockade of K_(V)1.3 channels in effector-memory T cellssuppresses activities like calcium signaling, cytokine production(interferon-gamma, interleukin 2) and cell proliferation.Effector-memory T cells (TEM) were originally defined by theirexpression of cell surface markers, and can enter sites of inflammationin non-lymphoid tissues, while not participating in the process oflymphoid recirculation carried out by most other lymphocytes. TEMs havebeen shown to uniquely express high numbers of the K_(V)1.3 potassiumchannel and depend on these channels for their function. In vivo,K_(V)1.3 blockers paralyze effector-memory T cells at the sites ofinflammation and prevent their reactivation in inflamed tissues. Incontrast, K_(V)1.3 blockers do not affect the homing to and motilitywithin lymph nodes of naive and central memory T cells, most likelybecause these cells express the KCa3.1 channel and are thereforeprotected from the effect of K_(V)1.3 blockade. Suppressing the functionof these cells by selectively blocking the K_(V)1.3 channel offers thepotential for highly effective therapy of autoimmune diseases withminimal effects on either beneficial immune responses or other organs(Chandy K. G. et al, Trends Pharmacol. Sci. 25(5): 280-9; Wulff H. etal, J. Clin. Invest. I I I (11): 1703-13; Beeton C. et al, Proc. Natl.Acad. Sci. U.S.A., 103(46): 17414-9; Matheu M. P. et al, Immunity 29(4):602-14). K_(v)1.3 has been reported to be expressed in the innermitochondrial membrane in lymphocytes. The apoptotic protein Bax hasbeen suggested to insert into the outer membrane of the mitochondria andocclude the pore of K_(V)1.3 via a lysine residue. Thus, K_(V)1.3blockade may contribute to apoptosis (Szabo I. et al, J. Biol. Chem.280(13): 12790-8; Szabo I. et al., Proc. Natl. Acad. Sci. U.S.A.105(39): 14861-6).

Autoimmune Disease is a family of disorders resulting from tissue damagecaused by a malfunctioning immune system, affecting tens of millions ofpeople worldwide. Such diseases may be restricted to a single organ, ase.g. in multiple sclerosis and Type I diabetes mellitus, or may involvemultiple organs as in the case of rheumatoid arthritis and systemiclupus erythematosus. Treatment is generally palliative and typicallyincludes anti-inflammatory and immunosuppressive drugs. The severe sideeffects of many of these therapies have fueled a continuing search formore effective and selective immunosuppressive drugs. Among these arethose which can selectively inhibit the function of effector-memory Tcells, known to be involved in the etiology of many of these autoimmunediseases and thereby ameliorate many autoimmune diseases withoutcompromising the protective immune response. Multiple sclerosis is adisease caused by autoimmune damage to the central nervous systemincluding the brain, which affects roughly two and a half million peopleworldwide. Symptoms include muscle weakness and paralysis, and thedisease can progress rapidly and unpredictably and may eventually leadto death. Treatment usually includes the use of anti-inflammatory andimmunosuppressive drugs which have potentially severe side effects.K_(V)1.3 has been shown to be highly expressed in autoreactive effectormemory T cells from MS patients (Wulff, H et al (2003) J Clin Invest111:1703-1713; Rus H et al (2005) PNAS 102:11094-11099). Animal modelsof multiple sclerosis have been successfully treated using blockers ofthe K_(V)1.3 potassium channel. In patients with multiple sclerosis,disease-associated myelin-specific T cells from the blood arepredominantly co-stimulation independent effector-memory T cells thatexpress high numbers of K_(V)1.3 channels. T cells in MS lesions inpostmortem brain lesions are also predominantly effector-memory T cellsthat express high levels of the K_(V)1.3 channel (Wulff H. et al, J.Clin. Invest. 111(11): 1703-13; Beeton C. et al, Proc. Natl. Acad. Sci.U.S.A. 103(46): 17414-9).

Type 1 diabetes mellitus is a disease caused by autoimmune destructionof insulin-producing cells in the pancreas, resulting in high bloodsugar and other metabolic abnormalities. Type 1 diabetes mellitusaffects close to four hundred thousand people in the US alone, and isusually diagnosed before age 20. Its long-term consequences may includeblindness, nerve damage and kidney failure, and left untreated israpidly fatal. Treatment involves life-long administration of insulin orpancreas transplantation, both of which may entail serious side effects(Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A. 103(46): 17414-9).

K_(v)1.3 is also considered a therapeutic target for the treatment ofobesity, for enhancing peripheral insulin sensitivity in patients withtype-2 diabetes mellitus, for preventing bone resorption in periodontaldisease, for rheumatoid arthritis, for inflammatory skin conditions,such as psoriasis, and for asthma (Tucker K. et al, Int. J. Obes. (Lond)32(8): 1222-32; Xu J. et al, Hum. Mol Genet. 12(5): 551-9; Xu J. et al,Proc. Natl. Acad. Sci. U.S.A. 101(9): 3112-7; Valverde P. et al, J.Dent. Res 84(6): 488-99; Tschritter O. et al, J. Clin. Endocrinol.Metab. 91(2): 654-8; Beeton, C. et al, Proc. Natl. Acad. Sci. U.S.A.103(46): 17414-17419; Azam, P. et al, J. Invest. Derm. 127: 1419-1429;Bradding, P et al, Br. J. Pharmacol. 157: 1330-1339).

Compounds which are selective K_(V)1.3 blockers are thus potentialtherapeutic agents as immunosuppressants or immune system modulatorsincluding for the prevention of graft rejection, and the treatment ofautoimmune and inflammatory disorders. K_(V)1.3 modulators may be usedalone or in conjunction with other immunosuppressants, such as selectiveKCa3.1 blockers or cyclosporin, in order to possibly achieve synergismand/or to reduce toxicity, especially of cyclosporin. At present thereexist a number of non-selective K channels that will inhibit lymphocyteproliferation, but have adverse side effects. Other K channels exist ina wide range of tissues including the heart and brain, and generallyblocking these channels is undesirable. U.S. Pat. No. 5,494,895discloses the use of a thirty-one amino acid peptide, scorpion peptidemargatoxin, as a selective inhibitor and probe of K_(V)1.3 channelspresent in human lymphocytes, and also as an immunosuppressant. Howeverthe use of this compound is limited by its potent toxicity.

International patent Application publications numbers WO 97/16438 and WO09/716437, and U.S. Pat. No. 6,051,590 describe the use of thetriterpene, correolide and related compounds as immunosuppressants inthe treatment of conditions in mammals affected or facilitated byK_(V)1.3 inhibition.

There is still a need for improved and specific therapies for immunediseases, including autoimmune diseases, and for immunosuppressiveagents which lack problematic side effects and specifically targetchannels involved in immune cell mediated actions.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) and relatedFormulae, and pharmaceutical compositions thereof. In certainembodiments compounds of Formula (I) have potency and selectivity in theprevention and treatment of conditions that have been associated withautoimmune disorders, immune-mediated disorders, inflammatory disorders,or other disorders, or conditions which benefit clinically fromimmunosuppressants, including multiple sclerosis, type-1 diabetesmellitus, type-2 diabetes mellitus, rheumatoid arthritis, systemic lupuserythematosus, psoriasis, contact dermatitis, obesity, graft-versus hostdisease, transplant rejection, and delayed type hypersensitivity. Inparticular, compounds, pharmaceutical compositions and methods providedare useful to treat, prevent or ameliorate a range of conditions inmammals such as, but not limited to, immune disorders and autoimmunediseases of various genesis or etiology, for example rheumatoidarthritis, multiple sclerosis, psoriasis, type 1 diabetes, graft-versushost disease, transplant rejection. In some embodiments, compounds,pharmaceutical compositions and methods provided are useful asantiinflammatory agents for the treatment of arthritis, and as agents totreat Parkinson's Disease, Alzheimer's Disease, asthma, myocardialinfarction, neurodegenerative disorders, inflammatory bowel disease andautoimmune disorders, renal disorders, obesity, eating disorders,cancer, schizophrenia, epilepsy, sleeping disorders, cognitivedisorders, depression, anxiety, blood pressure, and lipid disorders.

In one aspect the present invention provides compounds of Formula (I):

Wherein

-   G¹ denotes a single bond,-   G² denotes a CO group,-   X is selected from a single bond, an alkylene group having 1 to 6    carbon atoms optionally substituted with 1 or 2 substituents    selected from fluoro or C₁-C₆-alkyl,-   Y is selected from an alkylene group having 1 to 6 carbon atoms    optionally substituted one or two times with C₃-C₈-cycloalkyl or    C₁-C₃-alkyl; or a 3-8-membered cycloalkylene group,-   Q is selected from O, NH or a single bond,-   W is selected from SO, SO₂ or a single bond,-   U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of    the above groups being optionally substituted with 1 to 3    substitutents selected from Hal, NO₂, CN, —SO₂—C₁-C₆-alkyl,    —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a    5-6-membered heteroaromatic group being optionally substituted by    Hal,-   V is an aryl group optionally substituted with 1 to 3 substitutents    selected from Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,    O—C₁-C₆-halo-alkyl or a 5-6-membered heteroaromatic group,-   T denotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, or    pyrazolyl,-   R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl,-   R² and R^(2′) are independently from one another H, Hal,    —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or-   R¹ and R² are linked to form with the ring T to which they are    attached a 7-12-membered fused heterocyclyl or 7-12-membered fused    cycloalkyl, each of which may be optionally substituted with 1 to 3    Hal, —C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-alkyl, or —O—C₁-C₆-alkyl,-   R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or    —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a 3-8-membered cycloalkyl group,    optionally substituted with 1 to 3 substitutents independently    selected from Hal, —C₁-C₆-halo-alkyl, or C₁-C₆-alkyl; or a    3-8-membered heterocyclic group, optionally substituted with 1 to 3    substitutents independently selected from Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,    —SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or    —C(O)O—C₁-C₆-alkyl,-   R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³ a 3-8-membered    cycloalkyl ring, optionally substituted with Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl,-   m is selected from 1, 2, 3 or 4, preferably 1 or 2,-   Hal is F, Cl, Br, or I,    wherein -G²-Y—W together is at least 3 atoms in length,    as well as pharmaceutically acceptable salts thereof, or is an    enantiomeric mixture of 2 enantiomers in all ratios, and/or as a    mixture of diastereoisomers in all ratios.

In a second aspect, the present invention provides a kit or a setcomprising at least one compound of Formula (I) or related Formulae,preferably in combination with immunomodulating agents. Preferably, thekit consists of separate packs of:

-   -   (a) an effective amount of a compound of the Formula (I) and/or        pharmaceutically usable derivatives, solvates, salts, hydrates        and stereoisomers thereof, including mixtures thereof in all        ratios, and    -   (b) an effective amount of a further medicament active        ingredient.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising a compound provided herein, and a pharmaceuticalcarrier, excipient or diluent. The pharmaceutical composition cancomprise one or more of the compounds described herein. It will beunderstood that compounds provided herein useful in the pharmaceuticalcompositions and treatment methods disclosed herein, can bepharmaceutically acceptable as prepared and used.

In another aspect, the present invention relates to methods forpreventing, treating or ameliorating a condition from among those listedherein, particularly conditions that are associated with immune-mediatedreactions, autoimmune conditions, or other conditions which aremodulated by immunosuppression. Examples of these conditions aremultiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis,psoriasis, contact dermatitis, obesity, systemic lupus erythematosus,graft-versus host disease, and transplant rejection, which methodcomprises administering to a mammal in need thereof an amount of one ormore of the compounds provided herein, or pharmaceutical compositionthereof, effective to prevent, treat or ameliorate the condition.

In addition to the methods of treatment set forth above, the presentinvention extends to the use of any of the compounds of the inventionfor the preparation of medicaments that may be administered for suchtreatments, as well as to such compounds for the treatments disclosedand specified. In additional aspects, the present invention is directedto methods for synthesizing the compounds described herein, withrepresentative synthetic protocols and pathways described below.

Accordingly, it is an aim of this invention to provide new compoundswhich can modulate the activity of the voltage gated potassium channelK_(v) 1.3, and thus avert or treat any maladies that may be causallyrelated to aberrations in such activity.

The invention also provides a series of compounds that can treat oralleviate maladies or symptoms of same, such as immune-mediateddisorders and autoimmune diseases, that may be causally related to theactivation of the Kv1.3 channel.

The invention also provides a series of compounds that can treat adisease or condition, wherein the disease or condition is selected from:Acute disseminated encephalomyelitis (ADEM), Addison's disease,Allopecia areata, Alzheimers disease, Ankylosing spondylitis,Antiphospholipid antibody syndrome, Autoimmune hemolytic anemia,Autoimmune hepatitis, Autoimmune inner ear disease, AutoimmuneLymphoproliferative Syndrome (ALPS), Autoimmunepolyendocrine/polyglandular syndrome, Autoimmune thrombocytoipeniapurpura, Balo disease, Behcet disease, Bullous pemphigoid,Cardiomyopathy, Celiac sprue-dermatitis herpetiformis, Chronic fatigueimmune dysfunction syndrome (CFIDS), Chronic inflammatory demyelinatingneuropathy, Cicatrical pemphigoid, Coeliac disease, Cold agglutinindisease, CREST syndrome, Crohn's disease, Cystic fibrosis, Degosdisease, Dermatomyositis, Diabetes (Type I or Juvenile onset), Earlyonset dementia, Eczema, Endotoxin shock, Essential mixedcryoglobulinemia, Familial Mediterranean fever, Fibromyalgia,Fibromyositis, Goodpasture's syndrome, Graves' disease, Guillain-Barresyndrome (GBS), Hashimoto's thyroidosis, Hidradenitis suppurativa,Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgAnephropathy, Lambert-Eaton Myasthenic Syndrome, Leukemia, Lichen planus,Meniere disease, Mixed connective tissue disease, Multiple sclerosis,Multiphasic disseminated encephalomyelitis, Myasthenia gravis,Neuromyelitis Optica, Paraneoplastic Syndromes, Pemphigus, Pemphigusvulgaris, Pernicious anaemia, Polyarteritis nodosum, Polychondritis,Polymyalgia rhematica, Polymyositis, Primary agammaglobulinemia, Primarybiliary cirrhosis, Plaque Psoriasis, Psoriatic arthritis, Raynaudphenomenon, Reiter syndrome, Restenosis following angioplasty, Rheumaticfever, Rheumatoid arthritis, Rheumatoid psoriasis, Sarcoidosis,Scleroderma, Sepsis, Sezary's disease, Sjogren's syndrome, Stiff-personsyndrome, Systemic lupus erythematosis (SLE), Takayasu arteritis,Temporal arteritis (also known as “giant cell arteritis”), Transplant orAllograft rejection, Ulcerative colitis, Uveitis, Vasculitis, Vitiligo,Graft vs Host disease, pustular psoriasis, and Wegener's granulomatosis.

The invention further provides a series of compounds that can treat adisease or condition, wherein the disease or condition is selected from:resistance by transplantation of organs or tissue, graft-versus-hostdiseases brought about by medulla ossium transplantation, rheumatoidarthritis, systemic lupus, erythematosus, Hashimoto's thyroiditis,multiple sclerosis, myasthenia gravis, type I diabetes uveitis,juvenile-onset or recent-onset diabetes mellitus, posterior uveitis,allergic encephalomyelitis, glomerulonephritis, infectious diseasescaused by pathogenic microorganisms, inflammatory and hyperproliferativeskin diseases, psoriasis, atopical dermatitis, contact dermatitis,eczematous dermatitises, seborrhoeis dermatitis, Lichen planus,Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticariaangioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupuserythematosus, acne, Alopecia areata, keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical cornea, dystrophia epithelialis corneae,corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves'opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollenallergies, reversible obstructive airway disease, bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma,chronic or inveterate asthma, late asthma and airwayhyper-responsiveness, bronchitis, gastric ulcers, vascular damage causedby ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns and leukotriene B₄-mediateddiseases, Coeliac diseases, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis,eczema, interstitial nephritis, Good-pasture's syndrome,hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis,Guillain-Barre syndrome, Meniere's disease, polyneuritis, multipleneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow'sdisease, pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonenephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy; Pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C₄ release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis sclerosing cholangitis, partial liver resection, acuteliver necrosis, necrosis caused by toxin, viral hepatitis, shock, oranoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholiccirrhosis, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, augmentation ofchemotherapeutic effect, cytomegalovirus infection, HCMV infection,AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The invention further provides pharmaceutical compositions that areeffective in the treatment or prevention of a variety of disease states,including the diseases associated with the central nervous system,cardiovascular conditions, chronic pulmonary obstructive disease (COPD),inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, andother diseases where an immunological inflammatory component orautoimmune component is present.

In an embodiment, compounds of the present invention are used in thetreatment and prophylaxis of a condition selected from Multiplesclerosis, Rheumatoid arthritis, Psoriasis, Type 1 Diabetes, Type IIDiabetes, Systemic lupus nephritis, Oncology, Glomerulonephritis,Sjögrens's syndrome, Transplant rejection, Graft versus host disease,Allergic contact dermatitis, Neointimal hyperplasia/restenosis,Periodontal disease, Leprosy, and Obesity.

In another embodiment W is a single bond.

In another embodiment W is SO₂.

In an embodiment Q is a single bond.

In an embodiment Q is a single bond, and W is SO₂.

In an embodiment Q and W are single bonds.

In an embodiment G²-Y—W together is from 3-6 atoms in length.

In an embodiment G²-Y—W together is 3 atoms in length.

In an embodiment G²-Y—W together is 4 atoms in length.

In an embodiment G²-Y—W together is 5 atoms in length.

In an embodiment G²-Y—W together is 6 atoms in length.

In an embodiment G²-Y—W together is 3 atoms in length and W is a singlebond.

In an embodiment G²-Y—W together is 3 atoms in length and W is SO₂.

In an embodiment G²-Y—W together is 3 atoms in length and Q is a singlebond.

In an embodiment G²-Y—W together is 4 atoms in length and W is a singlebond.

In an embodiment G²-Y—W together is 4 atoms in length and W is SO₂.

In an embodiment G²-Y—W together is 4 atoms in length and Q is a singlebond.

In an embodiment G²-Y—W together is 5 atoms in length and W is a singlebond.

In an embodiment G²-Y—W together is 5 atoms in length and W is SO₂.

In an embodiment G²-Y—W together is 5 atoms in length and Q is a singlebond.

In an embodiment G²-Y—W together is 6 atoms in length and W is a singlebond.

In an embodiment G²-Y—W together is 6 atoms in length and W is SO₂.

In an embodiment G²-Y—W together is 6 atoms in length and Q is a singlebond.

In certain embodiments -G²-Y—W— is selected from one of the following:

In an embodiment V is an optionally substituted phenyl group.

In an embodiment V is an optionally substituted phenyl group, and Q is asingle bond.

In an embodiment V is an optionally substituted phenyl group, and W isSO₂—.

In an embodiment V is an optionally substituted phenyl group, Q is asingle bond, and W is SO₂—.

In an embodiment V is an optionally substituted phenyl group, Q and Ware single bonds.

Accordingly, in a further embodiment the invention relates to compoundsof formula (Ia):

wherein:

-   X is selected from a single bond, an alkylene group having 1 to 6    carbon atoms optionally substituted with 1 or 2 substituents    selected from fluoro or C₁-C₆-alkyl,-   Y is selected from an alkylene group having 1 to 6 carbon atoms    optionally substituted one or two times with C₃-C₈-cycloalkyl or    C₁-C₃-alkyl; or a 3-8-membered cycloalkylene group,-   Q is selected from O, NH or a single bond,-   V is an aryl group optionally substituted with 1 to 3 substitutents    selected from Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,    O—C₁-C₆-halo-alkyl or a 5-6-membered heteroaromatic group,-   U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of    the above groups being optionally substituted with 1 to 3    substitutents selected from Hal, NO₂, CN, —SO₂—C₁-C₆-alkyl,    —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a    5-6-membered heteroaromatic group being optionally substituted by    Hal,-   T denotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, or    pyrazolyl,-   R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl,-   R² and R^(2′) are independently from one another H, Hal,    —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or-   R¹ and R² are linked to form with the ring T to which they are    attached a 7-12-membered fused heterocyclyl or 7-12-membered fused    cycloalkyl, each of which may be optionally substituted with 1 to 3    Hal, —C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-alkyl, or —O—C₁-C₆-alkyl,-   R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or    —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a 3-8-membered cycloalkyl group,    optionally substituted with 1 to 3 substitutents independently    selected from Hal, —C₁-C₆-halo-alkyl, or C₁-C₆-alkyl; or a    3-8-membered heterocyclic group, optionally substituted with 1 to 3    substitutents independently selected from Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,    —SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or    —C(O)O—C₁-C₆-alkyl,-   R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³ a 3-8-membered    cycloalkyl ring, optionally substituted with Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl, and-   each m is independently selected from 1, 2, 3, or 4 preferably 1 or    2;    as well as pharmaceutically acceptable salts thereof, or is an    enantiomeric mixture of 2 enantiomers in all ratios, and/or as a    mixture of diastereoisomers in all ratios.

In relation to compounds of formula (Ia) the following furtherdefinitions may apply:

In an embodiment X is an alkylene group having 1 to 4 carbon atoms,optionally substituted with 1 or 2 substituents selected from fluoro orC₁-C₆-alkyl.

In an embodiment X is selected from methylene or ethylene.

In an embodiment X is methylene.

In an embodiment X is a single bond.

In an embodiment Y is an alkylene group having 1 to 4 carbon atoms,optionally substituted one or two times with C₃-C₈-cycloalkyl orC₁-C₃-alkyl.

In an embodiment Y is selected from methylene, ethylene, propylene,isopropylene, or tertbutylene.

In an embodiment Y is

In an embodiment Y is

In an embodiment Y is a 3-8-membered cycloalkylene group, or3-8-membered cycloalkenylene.

In an embodiment Y is a 3-membered cycloalkylene.

In an embodiment Y is

In an embodiment Y is

In an embodiment Y—W is

In an embodiment Y—W is

In an embodiment Y—W is

In an embodiment Y—W is

In an embodiment Y—W is

In an embodiment Q is a single bond.

Accordingly the invention contemplates compounds of the followinggeneral formulae:

wherein R¹, R², R^(2′), R³ and R⁴, T, Q, U and V are as defined abovefor compounds of formula (Ia).

In an embodiment the compound of the invention is a compound of formula(Ia^(I)).

In an embodiment the compound of the invention is a compound of formula(Ia^(II)).

In an embodiment the compound of the invention is a compound of formula(Ia^(III)).

In an embodiment the compound of the invention is a compound of formula(Ia^(IV)).

In an embodiment the compound of the invention is a compound of formula(Ia^(V)).

In an embodiment the compound of the invention is a compound of formula(Ia^(VI)).

In an embodiment the compound of the invention is a compound of formula(Ia^(I)), (Ia^(III)), (Ia^(VI)), wherein Q is a single bond.

In further embodiments the invention contemplates the following generalformulae:

wherein R¹, R², R^(2′), R³ and R⁴, T, U and V are as defined above forcompounds of formula (Ia).

In an embodiment the compound of the invention is a compound of formula(Ia^(Ia)).

In an embodiment the compound of the invention is a compound of formula(Ia^(IIIa)).

In an embodiment the compound of the invention is a compound of formula(Ia^(VIa)).

In still further embodiments the invention contemplates the followingfurther general formulae:

wherein R¹, R², R^(2′), R³ and R⁴, T, U and V are as defined above forcompounds of formula (Ia).

In a further embodiment, where W is a single bond, the invention relatesto compounds of formula (Ib) and salts thereof:

wherein:

-   X selected from a single bond, an alkylene group having 1 to 6    carbon atoms optionally substituted with 1 or 2 substituents    selected from fluoro or C₁-C₆-alkyl,-   Y is a 3-membered cycloalkylene group,-   Q is selected from O, NH or a single bond,-   V is an aryl group optionally substituted with 1 to 3 substitutents    selected from Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,    O—C₁-C₆-halo-alkyl or a 5-6-membered heteroaromatic group,-   U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of    the above groups being optionally substituted with 1 to 3    substitutents selected from Hal, NO₂, CN, —SO₂—C₁-C₆-alkyl,    —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a    5-6-membered heteroaromatic group being optionally substituted by    Hal,-   T denotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, or    pyrazolyl,-   R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl,-   R² and R^(2′) are independently from one another H, Hal,    —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or-   R¹ and R² are linked to form with the ring T to which they are    attached a 7-12-membered fused heterocyclyl or 7-12-membered fused    cycloalkyl, each of which may be optionally substituted with 1 to 3    Hal, —C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-alkyl, or —O—C₁-C₆-alkyl,-   R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or    —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a 3-8-membered cycloalkyl group,    optionally substituted with 1 to 3 substitutents independently    selected from Hal, —C₁-C₆-halo-alkyl, or C₁-C₆-alkyl; or a    3-8-membered heterocyclic group, optionally substituted with 1 to 3    substitutents independently selected from Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,    —SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or    —C(O)O—C₁-C₆-alkyl,-   R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³ a 3-8-membered    cycloalkyl ring, optionally substituted with Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl, and-   each m is independently selected from 1, 2, 3, or 4,    as well as pharmaceutically acceptable salts thereof, or is an    enantiomeric mixture of 2 enantiomers in all ratios, and/or as a    mixture of diastereoisomers in all ratios.

In an embodiment Q is a single bond.

In an embodiment Q and X are single bonds.

In an embodiment the present invention contemplates the followingfurther general formulae:

wherein R¹, R², R^(2′), R³ and R⁴, T, X, Q, U and V are as defined abovefor compounds of formula (Ib).

With reference to formula (Ib^(I)), the following further definitionsmay apply:

In an embodiment X is C₁-C₄ alkylene.

In an embodiment X is methylene, ethylene, propylene or isopropylene,

In an embodiment X is methylene or ethylene.

In an embodiment X is methylene.

In an embodiment the compounds of the invention may be represented bythe following general formula (Ib^(Ia)):

In still further embodiments the invention relates to compounds offormula (Ic) and salts thereof:

wherein:

-   X is selected from a single bond, an alkylene group having 1 to 6    carbon atoms optionally substituted with 1 or 2 substituents    selected from fluoro or C₁-C₆-alkyl,-   Y is an alkylene group having 1 to 6 carbon atoms,-   Q is selected from O, NH or a single bond,-   V is an aryl group optionally substituted with 1 to 3 substitutents    selected from Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,    O—C₁-C₆-halo-alkyl or a 5-6-membered heteroaromatic group,-   U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of    the above groups being optionally substituted with 1 to 3    substitutents selected from Hal, NO₂, CN, —SO₂—C₁-C₅₆-alkyl,    —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a    5-6-membered heteroaromatic group being optionally substituted by    Hal,-   T is a phenyl, a triazolyl, a thiazolyl, an oxazolyl, an    oxadiazolyl, or pyrazolyl group,-   R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl,-   R² and R^(2′) are independently from one another H, Hal,    —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or-   R¹ and R² are linked to form with the ring T to which they are    attached a 7-12-membered fused heterocyclyl or 7-12-membered fused    cycloalkyl, each of which may be optionally substituted with 1 to 3    Hal, —C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-alkyl, or —O—C₁-C₆-alkyl,-   R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or    —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a 3-8-membered cycloalkyl group,    optionally substituted with 1 to 3 substitutents independently    selected from Hal, —C₁-C₆-halo-alkyl, or C₁-C₆-alkyl; or a    3-8-membered heterocyclic group, optionally substituted with 1 to 3    substitutents independently selected from Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,    —SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or    —C(O)O—C₁-C₆-alkyl,-   R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³ a 3-8-membered    cycloalkyl ring, optionally substituted with Hal, —C₁-C₆-halo-alkyl,    NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,    —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl,-   each m is independently selected from 1, 2, 3, or 4,    as well as pharmaceutically acceptable salts thereof, or is an    enantiomeric mixture of 2 enantiomers in all ratios, and/or as a    mixture of diastereoisomers in all ratios.

In an embodiment Q is a single bond.

In an embodiment Q and X are single bonds.

In an embodiment the present invention contemplates the followingfurther general formulae:

wherein R¹, R², R^(2′), R³ and R⁴, T, Q, U and V are as defined abovefor compounds of formula (Ia).

In an embodiment in relation to formulae (Ic^(I)), (Ic^(II)), and(Ic^(III)) Q is a single bond.

In still a further embodiment the invention contemplates the followingfurther general formula:

wherein R¹, R², R^(2′), R³ and R⁴, T, U and V are as defined above forcompounds of formula (Ia).

With reference to Formulae (I), (Ia), (Ib) or (Ic) and each sub formula,the following further definitions may apply:

In an embodiment R⁴ is H or C₁-C₄ alkyl.

In an embodiment R⁴ is H.

In an embodiment R⁴ is C₁-C₄ alkyl.

In an embodiment R⁴ is methyl.

In an embodiment R³ is optionally substituted C₁-C₄ alkyl, or optionallysubstituted C₃-C₆ cycloalkyl.

In an embodiment R³ and R⁴ are independently C₁-C₃-alkyl.

In an embodiment R³ and R⁴ are both methyl.

In an embodiment R⁴ is hydrogen and R³ is tetrahydrofuranyl, azetidinyl,piperadinyl, or tetrahydropyranyl.

In an embodiment, the present invention provides compounds of Formulae(I), (Ia), (Ib) or (Ic) and each sub formula wherein R⁴ denotes H or Meand R³ is selected from the following groups:

wherein the above-mentioned groups may be further substituted by 1 to 3substitutents independently selected from Hal, —C₁-C₆-halo-alkyl, NO₂,CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-alkyl,—SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo- alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-halo-alkyl, or—O—C₁-C₆-halo-alkyl, or R⁴ forms together with R³ a 3 memberedcycloalkyl ring.

In an embodiment with specific reference to compounds of formula (Ia),(Ib), (Ic) and sub formula thereof, R⁴ is H and R³ is C₁-C₆ alkyl,cyclopropyl, or a 3-8-membered heterocyclic group.

In an embodiment with specific reference to compounds of formula (Ia),(Ib), (Ic) and sub formula thereof, R⁴ is H and R³ is C₁-C₆ alkyl orcyclopropyl.

In an embodiment with specific reference to compounds of formula (Ia),(Ib), (Ic) and sub formula thereof, R⁴ is H and R³ is cyclopropyl.

In an embodiment with specific reference to compounds of formula (Ia),(Ib), (Ic) and sub formula thereof, R⁴ is H and R³ is ethyl.

In an embodiment with specific reference to compounds of formula (Ia),(Ib), (Ic) and sub formula thereof, R⁴ is H and R³ is isopropyl.

In an embodiment with specific reference to compounds of formula (Ia),(Ib), (Ic) and sub formula thereof, R⁴ is H and R³ is methyl.

In an embodiment U is a 5-6-membered cycloalkyl group, a 5-12-memberedheterocyclyl or a 5-6 membered heteroaryl, each of the above groupsbeing optionally substituted with 1 to 3 substitutents selected fromHal, NO₂, CN, SO₂, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a 5-6-membered heteroaromaticgroup being optionally substituted by Hal.

In an embodiment U is selected from pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, imidazolyl, pyrazolyl, tetrahydropyranyl, cyclohexyl,8-azabicyclo[3.2.1]octan-3-yl, triazolyl and piperidinyl, each of theabove groups being optionally substituted with 1 to 3 substitutentsselected from Hal, NO₂, CN, SO₂, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a 5-6-membered heteroaromaticgroup being optionally substituted by Hal.

In an embodiment U is selected from pyridinyl, pyridazinyl andpyrazolyl, each of the above groups being optionally substituted with 1to 3 substitutents selected from CF₃, —SO₂—C₁-C₆-alkyl, C₁-C₆-alkyl orHal.

In an embodiment, U is selected from pyridinyl, pyridazinyl andpyrazolyl, each of the above groups being optionally substituted with asubstitutent selected from CF₃, —SO₂Me, methyl or F.

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein U is selected from:

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein U is selected from:

In an embodiment V is an aryl group optionally substituted with F to 3substitutents selected from Hal, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkylor SO₂—C₁-C₆ alkyl.

In an embodiment V is a phenyl group optionally substituted with 1 to 3substitutents selected from Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂,C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,O—C₁-C₆-halo-alkyl or a 5-6-membered heteroaromatic group.

In an embodiment V is a phenyl group optionally substituted with 1 to 3substitutents selected from Hal, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkylor SO₂—C₁-C₆ alkyl.

In an embodiment V is a phenyl group optionally substituted with 1 or 2substituents selected from F, Cl, —CF₃, —OCF₃, —OCHF₂ or —SO₂Me.

In an embodiment V is a phenyl group optionally substituted by F.

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein V is selected from:

Wherein R denotes Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl,O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, CF₃, or a 5-6-memberedheteroaromatic group.

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein V is selected from:

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein V is selected from:

In an embodiment T is phenyl, triazolyl, oxadiazolyl or diazolyl.

In an embodiment T is phenyl.

In an embodiment R¹ is O—C₁-C₆-alkyl, Hal, —(CH₂)_(m)—O—C₁-C₆-alkyl,—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,—SO₂-3-8-cycloalkyl, or cyano, in which m is 1.

In an embodiment R² and R^(2′) are H or Hal.

In an embodiment R² is H or Hal and R^(2′) is H.

In an embodiment R¹ is O—C₁-C₆-alkyl, Hal, —(CH₂)_(m)—O—C₁-C₆-alkyl,—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,—SO₂-3-8-cycloalkyl, or cyano, in which m is 1, R² is H or Hal andR^(2′) is H.

In an embodiment R¹ and R² are linked to form with the ring T to whichthey are attached a dihydrobenzofuranyl, an indanyl,

each of these groups being optionally substituted with 1 to 3 Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or—O—C₁-C₆-alkyl.

In an embodiment R¹ and R² are linked to form with the ring T to whichthey are attached a dihydrobenzofuranyl, an indanyl,

each of these groups being optionally substituted by 1 to 3—C₁-C₆-alkyl.

In an embodiment T is phenyl, triazolyl, oxadiazolyl or diazolyl; R¹ isO—C₁-C₆-alkyl, Hal, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-alkyl,O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,—SO₂-3-8-cycloalkyl, or cyano, in which m is 1; R² is H or Hal andR^(2′) is H; or R¹ and R² are linked to form with the ring T to whichthey are attached a dihydrobenzofuranyl, an indanyl,

each of these groups being optionally substituted by 1 to 3—C₁-C₆-alkyl.

In an embodiment T is phenyl, R¹ is O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkylor Hal, and R² and R^(2′) are H; or R¹ and R² are linked to form withthe ring T to which they are attached

which is optionally substituted with 1 or 2 —C₁-C₆-alkyl.

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein the group

is selected from:

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein the group

is selected from:

In a further embodiment, with specific reference to compounds of Formula(I), (Ia), (Ib), (Ic) and sub formula thereof the present inventionprovides wherein the group

is selected from:

In an embodiment, T is a phenyl ring wherein at least one of R¹, R² orR^(2′) is in para position with regard to the rest of the molecule.

In an embodiment, T is a phenyl ring wherein at least one of R¹, R² orR^(2′) is in meta position with regard to the rest of the molecule.

In an embodiment, T is a phenyl ring wherein at least one of R¹, R² orR^(2′) is in ortho position with regard to the rest of the molecule.

In one aspect, the present invention provides compounds of Formula (I)and related Formulae wherein

Hal preferably denotes F, Cl or Br, most preferably F, and/or

-   A 3-8-membered cycloalkyl group preferably is a cyclopropyl, a    cyclobutyl, or a cyclopentyl, and/or-   A 3-8-membered cycloalkylene group preferably is cyclopropylene, a    cyclobutylene, or a cyclopentylene, and/or-   A 3-8-membered heterocyclic group preferably has 1 to 3 carbon atoms    which is replaced by a group selected from O, S, N, SO, SO₂, CO. A    3-8-membered heterocyclic group preferably denotes one of the    following groups:

and/or

-   A 7-12 membered heterocyclic ring preferably denotes a bicyclic ring    having 7 to 12 carbon atoms wherein the 2 rings are fused or    bridged, and wherein 1 to 3 carbon atoms may be replaced by a group    selected from O, S, N, SO, SO₂, CO. A 7-12 membered heterocyclic    ring preferably denotes one of the following groups:

and/or

-   A 5-6-membered heteroaromatic group denotes an aromatic ring having    5 or 6 members and containing 1 to 3 heteroatoms selected from N, O    or S. A 5-6-membered heteroaromatic group preferably denotes one of    the following groups:

wherein these groups may be substituted according to the definitionsprovided above, and/or

-   A C₁-C₆-halo-alkyl denotes a linear or branched alkyl having 1 to 6    carbon atom wherein 1 to 6H atom is replaced by a halogen,    preferably a F atom.

In another aspect, the present invention provides compounds of Formula(II):

Wherein

-   G¹ denotes a single bond,-   G² denotes a CO group,-   X is selected from a single bond, an alkylene group having 1 to 6    carbon atoms optionally substituted with 1 or 2 substituents    selected from fluoro or C₁-C₆-alkyl,-   Y is selected from an alkylene group having 1 to 6 carbon atoms    optionally substituted one or two times with C₃-C₈-cycloalkyl or    C₁-C₃-alkyl; or a 3-8-membered cycloalkylene group,-   Q is selected from 0, NH or a single bond,-   W is selected from SO, SO₂ or a single bond,-   U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of    the above groups being optionally substituted with 1 to 3    substitutents selected from Hal, NO₂, CN, —SO₂—C₁-C₆-alkyl,    —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a    5-6-membered heteroaromatic group being optionally substituted by    Hal,-   V is an aryl group optionally substituted with 1 to 3 substitutents    selected from Hal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl,    O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,    O—C₁-C₆-halo-alkyl or a 5-6-membered heteroaromatic group,-   T denotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, or    pyrazolyl,-   R¹ is H, Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl,-   R² and R^(2′) are independently from one another H, Hal,    —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,    O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,    —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,    —(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or-   R¹ and R² are linked to form with the ring T to which they are    attached a 7-12-membered fused heterocyclyl or 7-12-membered fused    cycloalkyl, and optionally substituted with 1 to 3 Hal,    —C₁-C₆-halo-alkyl, NO₂, CN, a linear or branched alkyl group having    1 to 6 carbon atoms, —(CH₂)_(m)—O—C₁-C₆-alkyl, or —O—C₁-C₆-alkyl,-   R³ is C₁-C₆-alkyl,-   R⁴ is C₁-C₆-alkyl,-   m is selected from 1, 2, 3 or 4, preferably 1 or 2,-   Hal is F, Cl, Br, or I,-   wherein -G²-Y—W together is at least 3 atoms in length,    as well as pharmaceutically acceptable salts thereof, or is an    enantiomeric mixture of 2 enantiomers in all ratios, and/or as a    mixture of diastereoisomers in all ratios.

In an embodiment R³ is C₁-C₃-alkyl.

In an embodiment R⁴ is C₁-C₃-alkyl.

In an embodiment R³ and R⁴ are C₁-C₃-alkyl.

In an embodiment R³ is methyl.

In an embodiment R⁴ is methyl.

In an embodiment R³ and R⁴ are methyl.

In some embodiments G¹, G², X, Y, Q, W, U, V, T, R¹, R², R^(2′), m andHal are as defined above for a compound of Formula (I), (Ia), (Ib) or(Ic).

In an embodiment with specific reference to formula (II) R³ and R⁴ aremethyl and T is phenyl and R¹, R², and R^(2′) are all H.

In other aspects, in the kit or set, pharmaceutical composition, methodor use of the present invention described above a compound of Formula(II) may be present or used instead of a compound of Formula (I).

“Alkyl” refers to monovalent alkyl groups which may be straight chainedor branched. In certain embodiments an alkyl group has 1 to 6 carbonatoms (i.e., C₁-C₆-alkyl). In certain embodiments an alkyl group has 1to 4 carbon atoms (i.e., C₁-C₄-alkyl). In certain embodiments an alkylgroup has 1 to 3 carbon atoms (i.e., C₁-C₃-alkyl). Examples of suchalkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, n-hexyl, and the like.

“Alkylene” refers to divalent alkyl groups which may be straight chainedor branch chained. In certain embodiments the alkenylene group has 1 to6 carbon atoms. In certain embodiments 1 to 4 carbon atoms. In certainother embodiments 1 to 3 carbon atoms. In still further embodiments 1 or2 carbon atoms. Examples of such alkylene groups include methylene(—CH₂—), ethylene (—CH₂CH₂—), and the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—), and the like.

“Aryl” refers to an aromatic carbocyclic group having a single ring (eg.phenyl) or multiple condensed rings (eg. naphthyl or anthryl),preferably having from 6 to 14 carbon atoms. Examples of aryl groupsinclude phenyl, naphthyl and the like.

“Cycloalkyl” refers to cyclic alkyl groups having a single cyclic ringor multiple condensed or fused rings, preferably incorporating 3 to 12carbon atoms. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclooctyl, and the like, or multiple ring structures suchas adamantanyl, indanyl, 1,2,3,4-tetrahydronapthalenyl and the like.

“Cycloalkenyl” refers to cyclic alkenyl groups having a single cyclicring or multiple condensed or fused rings, and at least one point ofinternal unsaturation, preferably incorporating 3 to 8 carbon atoms.Examples of suitable cycloalkenyl groups include, for instance,cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl,indenyl and the like.

“Hal” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Heteroaryl” or “Heteroaromatic” refers to a monovalent aromaticheterocyclic group which fulfils the Hückel criteria for aromaticity(ie. contains 4n+2 π electrons) and preferably has from 2 to 10 carbonatoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium,and sulfur within the ring (and includes oxides of sulfur, selenium andnitrogen). Such heteroaryl groups can have a single ring (eg. pyridyl,pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (eg.indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl orbenzothienyl).

“Heterocyclyl” or “Heterocyclic” refers to a monovalent saturated orunsaturated group having a single ring or multiple condensed or fusedrings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atomsselected from nitrogen, sulfur, SO, SO₂, oxygen, selenium or phosphorouswithin the ring. In one embodiment, the heteroatoms are selected fromnitrogen, sulfur, SO, SO₂ and oxygen.

Examples of heterocyclyl and heteroaryl groups include, but are notlimited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine,imidazoline, piperidine, piperazine, indoline, phthalimide,1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene,thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole,thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl,pyrrolidine, tetrahydrofuranyl, triazole, and the like.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

The term “pharmaceutically acceptable cation” refers to an acceptablecationic counter-ion of an acidic functional group. Such cations areexemplified by sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium cations, and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

“Solvate” refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. This physical associationincludes hydrogen bonding. Conventional solvents include water, ethanol,acetic acid and the like. The compounds of the invention may be preparede.g. in crystalline form and may be solvated or hydrated. Suitablesolvates include pharmaceutically acceptable solvates, such as hydrates,and further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. ‘Solvate’ encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

It will also be recognised that compounds of the invention may possessasymmetric centres and are therefore capable of existing in more thanone stereoisomeric form. The invention thus also relates to compounds insubstantially pure isomeric form at one or more asymmetric centres eg.,greater than about 90% ee, such as about 95% or 97% ee or greater than99% ee, as well as mixtures in all ratios, including racemic mixtures,thereof. The compounds may also therefore appear as an enantiomericallyenriched mixture of two enantiomers in all ratios, and/or as a mixtureof diastereoisomers in all ratios. Such isomers may be prepared byasymmetric synthesis, for example using chiral intermediates, ormixtures may be resolved by conventional methods, eg., chromatography,or use of a resolving agent.

Furthermore, depending on the substitution pattern the compounds of thepresent invention may be capable of undergoing tautomerism. Accordingly,all possible tautomers of a compound of the present invention fallwithin the scope and spirit of the invention.

It would be appreciated that in certain embodiments a hydrogen atom maybe replaced with an isotope of hydrogen. For example, deuterium may beused to replace a metabolically labile hydrogen to improve thepharmacokinetics. Alternatively, tritium may be incorporated into acompound for diagnostic or analytical purposes, including but notlimited to biodistribution studies.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” includes that amount of a compound or composition that willelicit the biological or medical response of a subject that is beingsought by a medical doctor or other clinician. The “therapeuticallyeffective amount” can vary depending on the compound, the disease andits severity, and the age, weight, etc., of the subject to be treated.

“Preventing” or “prevention” refers to a reduction in risk of acquiringor developing a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a subject that may beexposed to a disease-causing agent, or predisposed to the disease inadvance of disease onset.

The term “prophylaxis” is related to “prevention”, and refers to ameasure or procedure the purpose of which is to prevent, rather than totreat or cure a disease.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting thedisease or reducing the manifestation, extent or severity of at leastone of the clinical symptoms thereof). In another embodiment ‘treating’or ‘treatment’ refers to ameliorating at least one physical parameter,which may not be discernible by the subject. In yet another embodiment,“treating” or “treatment” refers to modulating the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In a further embodiment, “treating” or “treatment” relates to slowingthe progression of the disease.

“Compounds of the present invention”, and equivalent expressions, aremeant to embrace compounds of the Formula(e) as hereinbefore described,which expression includes the prodrugs, the pharmaceutically acceptablesalts, and the solvates, e.g., hydrates, where the context so permits.Similarly, reference to intermediates, whether or not they themselvesare claimed, is meant to embrace their salts, and solvates, where thecontext so permits.

The inhibition data shown for the compounds of the list below wascalculated using the steady state current amplitude at the end of thedepolarising pulse in patch clamp evaluations (as described in theBiology Protocols: 1. Electrophysiology).

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts the crystal structure of(1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-cyclopropyl-(4-difluoromethoxy-phenyl)-methyl]-pyridazin-3-ylmethyl-amide.

FIG. 2 depicts the crystal structure of4-Bromo-N—[(R)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-benzamide.

GENERAL DESCRIPTION OF CHEMISTRY

Compounds of Formula (I) can be made by the reaction of the compounds ofFormula 5, wherein R¹, R², R^(2′), R³, R⁴, G¹, X, Q, T and U are asabove defined, with a compound of Formula 8, wherein G¹, Y, W and V areas above defined, and wherein LG denotes a suitable leaving group, asdepicted in scheme 1. LG preferably denotes an halogen, preferablychlorine or bromine, a sulfonate, or denotes an activated acidderivative obtained by the reaction of a carboxylic acid in the presenceof an amide coupling agent. The amide coupling agents include EDCI, BOP,PyBOP, HOBt, HATU, T3P, DCC. They can be used in a suitable solvent, asfor example dichloromethane or dimethylformamide at room temperature.Under preferred conditions, the secondary amines 5 is converted tocompounds of Formula (I) by reaction with an activated acid such as anacid chloride, in dichloromethane at room temperature, or a mixedanhydride or a N-succinimide ester in ethanol at room temperature or byreaction with an acid in the presence of an amide coupling reagentselected from EDCI, BOP, PyBOP, HOBt, HATU, T3P, DCC in dichloromethaneor dimethylformamide at room temperature.

Alternatively, compounds of Formula (I) can be synthesised by reacting acompound of Formula 7, wherein R¹, R², R^(2′), R³, R⁴, G², Y, W, T and Vare as above defined, with a compound of Formula 9, wherein G¹, X, Q, Uare as above define and wherein LG denotes a suitable leaving group.Examples of such alkanes having LG groups are alkyl halides or alkylsulfonates. The reaction of compounds of Formula 7 with compounds ofFormula 9 is preferably performed in the presence of a base such assodium hydride, potassium tert-butoxide, potassium carbonate preferablyin dimethylformamide or acetonitrile. The temperature of the reaction isbetween room temperature and 100° C., preferably between 20 and 60° C.Optionally, a phase transfer catalyst, such as tetra-n-butylammoniumbromide can be used. Preferred conditions are the use of acetone oracetonitrile with heating at 45-100° C.

When R⁴ is H, the compounds of Formula 5 can be synthesised by reactingketones 1, wherein R¹, R², R^(2′), R³ and T are as above defined, withamines 2, wherein G¹, X, Q and U are as above defined, according toscheme 2. This reaction is preferably performed by reductive aminationvia an imine intermediate.

Alternatively, when G¹ is a single bond, compounds of Formula 5, whereinR¹, R², R^(2′), R³, R⁴, X, Q, T and U are as defined above, may besynthesised by reacting a compound of Formula 3, wherein R¹, R², R^(2′),R³, R⁴ and T are as above defined, with the aldehyde of Formula 4,wherein Q and U are as above defined, and wherein X′ denotes a linear orbranched alkyl having 1 to 6 carbon atom or a cyclic alkyl having 3 to 8carbon atoms wherein 1 —CH₂— group, in this linear, branched or cyclicalkyl, is replaced by a —CO— group.

The reductive amination reaction described in scheme 2 can occur in asingle pot reaction using borohydride reagants, including but notlimited to sodium cyanoborohydride, sodium acetoxyboro-hydride andsodium borohydride in halogenated solvents such as dichloromethane or1,2-dichloroethane, or alcohols such as methanol, typically at roomtemperature for 0.5-12 hours.

The reaction can also occur in two steps. Firstly by the formation ofimine in the presence of an acid including but not limited top-toluenesulfonic acid, or Amberlyst resin and also a dehydratingreagent, such as but not limited to magnesium sulphate, sodium sulphate,molecular sieves or TiCl₄ using for example dichloromethane, ethanol,ethyl acetate or dimethyl sulfoxide as solvent. This step may beperformed in a Dean Stark apparatus using toluene at 90-110° C. In asecond step, the imine can be converted to the secondary amine usingborohydride reagents as described above.

Secondary amines 5 may be prepared by the alkylation of primary amines 2with a compound of Formula 6 or the amine 3 with a compound of Formula10, wherein LG in Formulae 6 and 10 denotes a suitable leaving group.Such suitable leaving groups may be selected from halogen, preferablychlorine or bromine, or a sulfonate group, preferably selected frommesylate, tosylate, benzyl sulphonyl, a perfluoroalkyl sulfonate such asmono, di or trifluoromethyl sulfonate or triflate. The reaction ispreferably performed in the presence of a base, such as potassiumcarbonate or triethylamine, in solvents preferably selected fromdichloromethane, acetonitrile, dimethyl sulfoxide, at temperaturesranging from room temperature to 100° C., As disclosed in scheme 3.

Compounds of Formula 7 may be prepared by reacting a compound of Formula3, wherein R¹, R², R^(2′), R³, R⁴ and T are as above defined, with acompound of Formula 8, wherein G², Y, W, and V are as above defined, andwherein LG is as defined above, as mentioned in scheme 4.

Amines of Formula 3 can be acylated with compounds of Formula 8, usingtechniques well known in the art. For this purpose, LG in the compoundsof Formula 8 is preferably an activated acid obtained by reaction of aCOOH group in the presence of an amide coupling reagent. The amidecoupling reagents include EDCI, BOP, PyBOP, HOBt, HATU, T3P, DCC. Theycan be used in a suitable solvent, as for example dichloromethane ordimethylformamide at room temperature.

Amines 3 wherein R⁴ is H can be prepared by functional grouptransformations well known in the art. Non-limiting examples areprovided in Scheme 5. Ketones 11 can be condensed with hydroxylamine,for instance in ethanol at 80-100° C. for 1-2 days to give 12, which canin turn be reduced to amine 3 using for example Raney nickel in methanolat 80-100° C. for 2-6 hours, or by hydrogenation using palladium oncharcoal for instance in ethanol at room temperature for 1-12 hours.Aldehydes 13 can be treated with metallated alkyl species such asGrignard reagents or alkyl lithiums to give secondary alcohols 14 forinstance in diethylether or tetrahydrofuran at −78° C. for 1-4 hours,which can be converted to azides 15 using techniques known in the art,for instance by reaction with sodium azide in chloroform and sulfuricacid at 0° C. to room temperature. The azides can be reduced to theamines 3 for example by catalytic hydrogenation with palladium oncharcoal in methanol at room temperature or by using PPh₃/H₂O(Staudinger conditions). Reaction of benzonitriles 16 with Grignardreagents or alkyl lithiums for example diethyl ether or tetrahydrofuranat room temperature to 50° C. for 1-4 hours can give imines 17, whichmay be reduced for instance with sodium borohydride in methanol at roomtemperature or lithium aluminium hydride in dimethyl formamide at roomtemperature or borane-THF complex in tetrahydrofuran at −20° C. to roomtemperature to give the amines 3.

Chemistry Protocols

The following abbreviations refer to the abbreviations used below:

AcOH (acetic acid), CAN (acetonitrile) BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene), dba (dibenzylideneacetone), bs (broad singlet), iBu (iso-butyl), tBu (tert-Butyl), tBuOK(potassium tert-butoxide), m-CPBA (meta-chloroperbenzoic acid); CDI(1,1′-Carbonyldiimidazole), cond. (conditions), DAST(diethylaminosulfurtrifluoride), DBU(1,8-dizabicyclo[5.4.0]undec-7-ene), DCM (dichloromethane), DEA(diethylamine), DIAD (diisobutylazodicarboxylate), DIEA (di-isopropylethylamine), DMA (dimethyl acetamide), DMAP (4-dimethylaminopyridine),DMSO (dimethyl sulfoxide), DMF (N,N-dimethylformamide), DPPA(diphenylphosphoryl azide), d (doublet), EDC.HCl(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), eq.(equivalents), EtOAc (ethyl acetate), EtOH (ethanol), g (gram), Gen.(General Procedure), cHex (cyclohexane), HPLC (high performance liquidchromatography), hr (hour), IPA (isopropyl alcohol), int.(intermediate), LCMS (liquid chromatography-mass spectrometry), MHz(Megahertz), MeOH (methanol), min (minute), mL (milliliter), mmol(millimole), mM (millimolar), mp (melting point), MS (massspectrometry), MTBE (methyl tert-butyl ether), MW (microwave), NMM(N-methyl morpholine), m (multiplet), NMR (Nuclear Magnetic Resonance),NBS (N-bromo succinimide), PBS (phosphate buffered saline), PDA(photodiode array), PMB (para-methoxybenzyl), cPr (cyclo-propyl), iPr(iso-propyl), PTLC (preparative thin layer chromatography), Rt(retention time), RT (room temperature), TBAF (tetra-butylammoniumfluoride), TBTU (N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uroniumtetrafluoroborate), T3P (propane phosphonic acid anhydride), TEA(triethyl amine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), t(triplet), PetEther (petroleum ether), TBME (tert-butyl methyl ether),TLC (thin layer chromatography), TMS (trimethylsilyl), TMSI(trimethylsilyl iodide), UV (ultraviolet), # of iso. (number ofstereoisomers).

The compounds of invention have been named according to the standardsused in the program ACD/Name Batch from Advanced Chemistry DevelopmentInc., ACD/Labs (7.00 Release). Product version: 7.10, build: 15 Sep.2003. NMR, HPLC and MS data provided in the examples described below areregistered on:

NMR: Bruker DPX-300 (300 MHz) or Varian Gemini 2000 (300 MHz) usingresidual signal of deuterated solvent as internal reference.

HPLC: Method 1—Waters Alliance 2695, column Waters XBridge C8 3.5 μm4.6×50 mm, conditions: solvent A (H₂O with 0.1% TFA), solvent B (ACNwith 0.05% TFA), gradient 5% B to 100% B over 8 min, UV detection withPDA Water 996 (230-400 nm).

LCMS: Method 2—Agilent 1100 Series LC/MSD, column Phenomenex Gemini-NXC18 5 m, Zorbax Eclipse XBD-C8 or Luna 5 μm C8, 150×4.6 mm, with mobilephase 80% ACN, 15% H₂O, 5% buffer (3:1 MeOH/H₂O, 315 mg HCO₂NH₄, 1 mLAcOH) and MS detection (ESI method).

UPLC: Method 3—Waters Acquity, column Waters Acquity UPLC BEH C18 1.7 m2.1×50 mm, conditions: solvent A (10 mM ammonium acetate in water+5%ACN), solvent B (ACN), UV detection (PDA, 230-400 nm) and MS detection(SQ detector, positive and negative ESI modes, cone voltage 30 V).Gradient 5% B to 100% B over 3 min or gradient 40% B to 100% B over 3min.

MD Autoprep: preparative HPLC purifications are performed with a massdirected auto-purification Fractionlynx from Waters equipped with aSunfire Prep C18 OBD column 19×100 mm or 30×100 mm 5 m, unless otherwisereported. All HPLC purifications were performed with a gradient ofACN/H₂O or ACN/H₂O/HCOOH (0.1%).

Preparative Chiral Separation of Example Compounds: preparative SFC/HPLCpurifications were performed using the columns and conditions listedbelow (250×20 mm).

A=SFC Chiralpak 1A (35-40° C., 10-20% MeOH or EtOH in heptane, 60-80mL/min)

B=SFC Chiralpak 1C (40° C., 15-30% MeOH, EtOH or IPA in heptane (with upto 0.1% DEA), 60-100 mL/min)

C=SFC Chiralpak AD-H (40° C., 7% EtOH in heptane, 60 mL/min)

D=SFC ChiralCel ODH (40° C., 10-20% MeOH or EtOH in heptane (with up to0.1% DEA), 60-80 mL/min)

E=HPLC ChiralCel ODH (20% IPA in heptane, with 0.1% DEA, 10 mL/min)

F=HPLC Chiralpak 1C (20-50% EtOH or IPA in heptane with 0.1% DEA, 10-20mL/min)

G=HPCL Chiralpak 1A (100% EtOH or 20% EtOH or IPA in heptane with either0.1% DEA or 0.37% DCM and 0.19% acetone, 10 mL/min)

H=HPLC Chiralpak AYH (20% IPA in heptane 10 mL/min)

I=SFC Chiralcel OJH (35-40° C., 20% MeOH in heptane, 60-80 mL/min)

J=HPLC Chiralpak AYH (20% EtOH in heptane with 0.1% DEA, 10 mL/min)

EXAMPLES AND GENERAL PROCEDURES General Procedures

General Procedure A: Reductive Amination of Aldehydes/Ketones toSec-Amines Using Triacetoxyborohydride

To a solution of aldehyde/ketone (1 eq.) and amine (1-2.5 eq.) inanhydrous DCE (˜0.1M), sodium triacetoxyborohydride (1.5-3.0 eq.) andwith or without acetic acid (2-3 eq.) were added sequentially and theresulting reaction mixture was stirred under a nitrogen atmosphere at RTuntil completion. The crude reaction mixture was diluted with EtOAc andthe organics washed with a NaHCO₃ (aq.) solution or 1M NaOH followed bydistilled water. The organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure to provide the crude product, whichwas used without purification to the next step or purified by MDAutoprep or by silica-gel column chromatography using increasinggradient of EtOAc or/and MeOH in hexane or DCM as eluant to afford thesecondary amine.

General Procedure B: Reductive Amination of Aldehydes/Ketones toSec-Amines Using p-Toluenesulfonic Acid and Dean-Stark Apparatus

To a solution of aldehyde/ketone (1 eq.) and amine (1-4 eq.) in toluene(2-5 M) was added p-toluenesulfonic acid (0.1 eq.) and resulting mixturewas heated to reflux under Dean-Stark conditions. After the formation ofthe imine intermediate (TLC/LCMS), solvent was removed under reducedpressure and the resulting residue was dissolved in MeOH or DCM. Sodiumborohydride or sodium triacetoxyborohydride was added and reactionmixture was stirred at RT under a nitrogen atmosphere. Upon completionof the reaction (LCMS), the solvent was removed under reduced pressureand the resulting residue was diluted with EtOAc or DCM and the organicswashed with saturated NH₄Cl (aq.) solution or 1M NaOH followed bydistilled water. The organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure to give the crude product, which wasused without purification to the next step or purified by MD Autoprep orby flash chromatography (silica-gel, EtOAc) to afford the secondaryamine.

General Procedure C: Preparation of t-Amides from Acid Chlorides

Triethylamine or diisopropylethylamine (2 eq.) was added to a solutionof sec-amine (1 eq.) in anhydrous DCM or Et₂O (0.1-0.3M) and theresulting solution was stirred at RT under a nitrogen atmosphere for 5min. Acid chloride (1.5-2.5 eq.) was added and the reaction mixture wasstirred until completion (LCMS). The reaction mixture was diluted withEtOAc or diethyl ether and washed thoroughly with NaHCO₃ (aq.) solutionfollowed by distilled water. The organic layer was separated, dried(MgSO₄) and concentrated under reduced pressure. The crude material waspurified using either PTLC or silica-gel flash chromatography usingincreasing gradient of EtOAc or/and MeOH in hexane or DCM as eluant.

General Procedure D: Preparation of Tertiary-Amides from Acids

To a solution of sec-amine (1 eq.) with or without triethylamine (1-1.5eq.) and acid (1-6 eq.) in anhydrous DCE (0.22-0.28M) at 0° C. or RT,was added 1-propylphosphonic acid cyclic anhydride (T3P) (1-4 eq.) undera nitrogen atmosphere. The mixture was allowed to stir at RT or refluxuntil reaction completion (LCMS). The reaction was quenched by theaddition of 1M NaOH and extracted with EtOAc or DCM. Organic layer waswashed sequentially with 1M NaOH and then with 1M HCl, filtered, dried(MgSO₄) and concentrated under reduced pressure, to obtain a yellow oil,which was purified using PTLC and/or silica-gel flash chromatography orwas used without purification to the next step or by MD Autoprep.

General Procedure E: Formation of Sulfonamides

To a mixture of potassium carbonate (2 eq.) in anhydrous acetonitrile(0.1-0.4 M) were added the sec-amine (1 eq.) and the sulfonyl chloride(1.5-2.5 eq.) sequentially under nitrogen atmosphere. The resultingmixture was heated to reflux until reaction completion (LCMS). Solventwas removed under reduced pressure and the reaction mixture was dilutedwith EtOAc and washed thoroughly with NaHCO₃ (aq.) solution followed bydistilled water. The organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure. The crude material was purifiedusing either PTLC or silica-gel flash chromatography using increasinggradient of EtOAc or/and MeOH in hexane or DCM as eluant.

General Procedure F: Deprotection of Acetal

A solution of acetal (1 eq.) in a mixture of CH₃CN/H₂O/TFA (1/1/0.04)(0.1-0.5 M) was stirred at RT for 18 hr. The reaction was diluted withDCM and was then washed sequentially with 1M HCl, 1M NaOH and brine. Theorganic was dried (MgSO₄), filtered and concentrated under reducedpressure and the crude material purified by column chromatography orused directly to the next step without further purification.

General Procedure G: Swern-Oxidation of Alcohols to Aldehydes

Oxalyl chloride (1.5 eq.) was added slowly to a solution of anhydrousdimethylsulfoxide (3.0 eq.) in anhydrous DCM (0.17-2.0M) at −78° C.under a nitrogen atmosphere and stirred for 30 min. To the resultingmixture, was added the alcohol (1 eq.) dissolved in anhydrous DCM(0.2-0.4M) and the reaction mixture was stirred at −78° C. for 45 min.Anhydrous triethylamine (6 eq.) was added drop-wise and reaction wasstirred at −78° C. for 30 min and then at RT for 30 min. The DCM wasremoved under reduced pressure and residue was dissolved in diethylether and washed with NH₄Cl (aq.) solution. The organic layer wasseparated and the aqueous layer was again extracted with diethyl ether.The organic layers were combined, dried (MgSO₄), filtered andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography.

General Procedure H: Alkylation of Sec-Amines

To the solution of sec-amine (1 eq.) in anhydrous DCM (˜0.14M) was addedsequentially DIPEA (1.2-1.5 eq.) and chloroacetylchloride (1.1-1.4 eq.)and the resulting mixture was stirred at RT under a nitrogen atmosphereuntil completion. The reaction was quenched with water and extractedwith DCM. The combined organics were dried (MgSO₄) and concentratedunder reduced pressure. Crude material was purified using PTLC and/orsilica-gel column chromatography.

General Procedure I: Preparation of t-Amides

To a solution of amide (1 eq.) and amine (2-2.5 eq.) in anhydrous DMF(0.11-0.12M) was added Na₂CO₃ (2-2.5 eq.) and sodium iodide (1-1.1 eq.)sequentially and the resulting mixture was stirred at 65° C. overnight.The reaction mixture was cooled to RT and diluted with diethyl ether andwashed with water. Organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure. Crude material was purified usingsilica-gel column chromatography.

General Procedure J: Preparation of Acid Chlorides

A suspension of acid in thionyl chloride (0.4-0.6M) was stirred at RTovernight or refluxed for 1 h. Excess thionyl chloride was removed underreduced pressure at RT and traces were removed under reduced pressure. Aclear oil of acid chloride was obtained, which was used without furtherpurification.

Or

To a solution of the acid and DMF (cat) in anhydrous DCM at 0° C. wasadded a solution of oxalyl chloride (3 eq.) in anhydrous DCM, dropwise.The reaction mixture was stirred for 1 hr at 0° C., before warming to RTand stirring for a further 1 hr. The reaction mixture was concentratedunder reduced pressure and used without further purification.

General Procedure K: Reductive Amination of Ketones with Amine.HCl toSec-amines using Ti(OiPr)₄ and NaBH₃(CN)

To a suspension of the amine.HCl salt (1.5 eq.) in THF was added DIPEA(1.5 eq.), the ketone (1 eq.) and Ti(OiPr)₄ and the reaction mixtureheated to 50° C. in a sealed tube ON. The reaction mixture was cooled toRT and a solution of NaBH₃(CN) (2 eq.) in MeOH was added and thereaction mixture heated to 50° C. ON. The reaction mixture was cooledand diluted with Et₂O and quenched with NaOH (1M). The biphasic solutionwas filtered through Celite and the phases separated before extractingthe aqueous phase with EtOAc (2×). The combined extracts were dried(MgSO₄) and concentrated under reduced pressure to provide the crudeproduct which was used without purification in the next step or purifiedby silica-gel column chromatography using the appropriate solvent.

General Procedure L: Reductive Amination of Aldehydes/Ketones toSec-Amines Using Sodium Borohydride

To a solution of the ketone/aldehyde (1 eq.) and the amine (1. eq) inTHF (0.2M) at RT was added MgSO₄ (2.5 eq.). The reaction was monitoredby LCMS/TLC for completion of imine formation (heated to 60° C. ifrequired). Upon completion the reaction mixture was filtered throughCelite and concentrated under reduced pressure. The imine was taken upin MeOH (0.2M) and NaBH₄ was added at RT. The reaction was monitored byLCMS/TLC. Upon complete reduction of the imine the reaction mixture wasdiluted with NH₄Cl (sat. aq.) and the product extracted with DCM (3×).The combined extracts were dried (MgSO₄) and concentrated under reducedpressure to provide the crude product which was used withoutpurification in the next step or purified by silica-gel columnchromatography using the appropriate solvent.

General Procedure M: Preparation of t-Amides from Acid Chlorides inPyridine

To a solution of the acid chloride (1.5 eq.) in pyridine (0.2M) wasadded a solution of the amine (1 eq.) in pyridine followed by DMAP (0.2eq.). The reaction mixture was stirred until complete (by LCMS or TLC).The reaction mixture was concentrated under reduced pressure and dilutedwith Et₂O. The organics were washed with H₂O (3×) and NH₄Cl (sat. aq.,1×) before stirring vigorously with K₂CO₃ (2M) for 1 hr. The phases werethen separated and the organics dried (MgSO₄) and concentrated underreduced pressure. The crude material was purified by either PTLC orsilica-gel flash column chromatography using the appropriate solvent.

General Procedure N: Liberation of N-Tert-Butoxycarbonyl ProtectedAmines Using TMSI.

To a solution of the N-tert-butoxycarbonyl derivative in CHCl₃ (0.2M) atRT was added TMSI, dropwise. The solution was stirred for 5 minutes atRT before quenching by addition of a couple of drops of MeOH followed byNaHCO₃ (sat. aq.). The product was extracted into DCM (3×) and thecombined extracts dried (MgSO₄) and concentrated under reduced pressure.The crude material was purified by PTLC and/or silica-gel flash columnchromatography using the appropriate solvent.

General Procedure O: Liberation of N-Tert-Butoxycarbonyl ProtectedAmines Using TFA

To solution of the N-tert-butoxycarbonyl derivative in DCM or DCE (0.5M)was added TFA at RT and the reaction mixture stirred. The reactionprogress was monitored by TLC/LCMS and upon completion the reaction wasquenched by addition of NaHCO₃ (sat. aq.). The product was extractedwith DCM (3×) and the combined extracts dried (MgSO₄) and concentratedunder reduced pressure. The crude material was either used withoutpurification in the next step or purified by either PTLC or silica-gelflash column chromatography using the appropriate solvent.

Note: for particularly unreactive analogues microwave irradiation of theabove solution at 120° C. for 5 minutes produced the desired product.

General Procedure P: Liberation of N-Tert-Butoxycarbonyl ProtectedAmines Using HCl

The N-tert-butoxycarbonyl derivative was dissolved in a solution of HClin Et₂O. After several minutes a precipitate formed and LCMS was used tomonitor the reaction progress. Upon completion the precipitate wascollected by vacuum filtration and the product re-crystallised fromDMC/Et₂O.

General Procedure Q: N-Methylation Via Reductive Amination of an Amineand Formaldehyde with Sodium Triacetoxyborohydride or SodiumCyanoborohydride.

To a solution of the amine in MeOH (0.2M) was added AcOH andformaldehyde (37% in H₂O). The reaction mixture was stirred at RT for 30min before addition of NaHB(OAc)₃ or NaBH₃(CN). The reaction wasmonitored by LCMS/TLC and following completion was quenched with NaHCO₃(sat. aq.). The product was extracted with EtOAc (3×) and the combinedextracts dried (MgSO₄) and concentrated under reduced pressure. Thecrude material was purified by either PTLC or silica-gel flash columnchromatography using the appropriate solvent.

General Procedure R: Pyridine N-Oxide Formation Using m-CPBA

To a solution of the pyridine analogue in DCM (0.1M) at 0° C. was addedm-CPBA (1.2 eq.) and the reaction mixture warmed to RT. The reactionprogress was monitored by TLC/LCMS and upon completion the reactionmixture was diluted with EtOAc and washed with NaOH (1M, 3×), brine(1×), dried (MgSO₄) and concentrated under reduced pressure. The crudeproduct was purified by pTLC or silica-gel flash column chromatographyusing the appropriate solvent.

General Procedure S: Amine Formation Using CH₃CO₂NH₄ and NaBH₃(CN)

To a solution of the ketone analogue in MeOH (0.1M) was added ammoniumacetate (10 eq.) and NaBH₃(CN) (4 eq.). The reaction mixture was heatedat reflux for 18 hours. The reaction mixture was cooled to RT andconcentrated under reduced pressure and the crude residue partitionedbetween 1M NaOH and EtOAc. The layers were separated and the aqueousfurther extracted with EtOAc (2×). The extracts were combined, driedover MgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by silica-gel flash column chromatography using theappropriate solvent.

General Procedure T: Conversion of 6-Bromopyridine to 6-alkylsulfone

Step i) To a suspension of NaH 60% in mineral oil (1.2 eq) in dry DMF(0.1M) under N₂ at RT was added the appropriate thiol (1.2 eq.)drop-wise. After stirring at this temperature for 10 min. a solution ofthe 6-bromopyridine analogue in dry DMF (0.1M) was added drop-wise andthe reaction heated to 60° C. The reaction was monitored by LCMS/TLC andfollowing completion was quenched with sat.NH₄Cl. The product wasextracted with EtOAc (3×) and the combined extracts dried (MgSO₄) andconcentrated under reduced pressure. The crude material was purified byeither PTLC or silica-gel flash column chromatography using theappropriate solvent to obtain the thiopyridine intermediate.

Step ii) To a solution of the thiopyridine intermediate in dry DCM(0.1M) under N₂ at 00° C. was added m-CPBA (2 eq) portion-wise. Thereaction was monitored by LCMS/TLC and following completion was quenchedwith sat.NaHCO₃. The product was extracted with EtOAc (3×) and thecombined extracts dried (MgSO₄) and concentrated under reduced pressure.The crude material was purified by either PTLC or silica-gel flashcolumn chromatography using the appropriate solvent

General Procedure U: Preparation of t-Amides Using HATU

To a solution of acid (1.05 eq.) and DIPEA (2.1 eq.) in anhydrous DMF (8mL per 200 mg acid) at 0° C. under a nitrogen atmosphere was added HATU(1.1 eq.) followed by amine (1 eq.). The mixture was stirred at thistemperature for 3 hr. and then brought to ambient temperature andstirred for 16 hr. Once complete the reaction was diluted with EtOAc andextracted with water×1, sat. NaHCO₃×1 and brine×1, the combined organicswere then dried (MgSO₄), filtered, concentrated under reduced pressureand purified by column chromatography eluting with 5% diethyl ether inDCM.

General Procedure Y: Reductive Amination of Aldehydes/Ketones toSec-Amines Using Sodium Cyanoborohydride

To a solution of the ketone/aldehyde (1 eq.) and the amine (0.9 eq) inDCE (0.2M) at RT was added a solution of sodium cyanoborohydride (4 eq)in MeOH (0.8 M) in three portions within 2 hours and reaction mixturewas stirred overnight at RT. The reaction was quenched by addition ofsodium bicarbonate (sat. aq.) and extracted with EtOAc. The organiclayer was washed with brine, dried over MgSO₄ and concentrated underreduced pressure. The crude material was purified by silica-gel flashchromatography using 10% MeOH in 1/1 DCM/Diethyl ether mixture aseluent.

General Procedure AD: Modified Reductive Amination with Acetone

To a solution of amine (1 eq.) in anhydrous THF (1 mL per 100 mg amine)was added acetone (4 eq.) followed by Ti(OPr^(i))₄ (1.4 eq.) and thevessel sealed and heated to 40° C. for 2 hr. After this time thevolatiles were removed under a stream of nitrogen and methanol (1 mL per200 mg amine) was added to the residue. To this was added acetone (1eq.) followed by NaBH₃CN (2 eq.) and the vessel sealed and heated to 40°C. for 2 hr. Once complete the mixture was diluted with EtOAc andquenched with minimal sat. NaHCO₃ solution, the mixture was thenfiltered through Celite washing with EtOAc. The filtrate was thenextracted with sat. NaHCO₃ solution×1 and the organics dried (MgSO₄),concentrated under reduced pressure and the crude material used.

Intermediate a1-cyclopropyl-1-(4-methoxyphenyl)-N-(pyridin-2-ylmethyl)methanamine

Cyclopropyl-4-methoxyphenyl ketone (1 g, 5.67 mmol) and 2-(aminomethyl)pyridine (1.18 mL, 11.35 mmol), were reacted according to GeneralProcedure A to afford the title compound as a pale yellow oil. ¹H NMR(CDCl₃) δ 8.56-8.55 (m, 1H), 7.63-7.57 (dt, J=1.5, 7.8 Hz, 1H),7.33-7.29 (m, 2H), 7.19-7.12 (m, 2H), 6.91-6.87 (m, 2H), 3.81 (s, 3H),3.81-3.68 (m, 2H), 2.77 (d, J=9.0 Hz, 1H), 1.65 (bs, 1H), 1.19-1.16 (m,1H), 0.66-0.56 (m, 1H), 0.43-0.27 (m, 2H), 0.21-0.14 (m, 1H). MS (ES⁺)m/z 269.2 (M+H)⁺.

Intermediate b1-cyclopropyl-1-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)methanamine

4-Chlorophenyl cyclopropylketone (500 mg, 2.77 mmol) and 2-(aminomethyl)pyridine (1.151 mL, 11.17 mmol) were reacted according to GeneralProcedure B to afford title compound as a pale yellow oil. ¹H NMR(CDCl₃) δ 8.57 (m, 1H), 7.63-7.57 (m, 1H), 7.35-7.29 (m, 4H), 7.17-7.12(m, 2H), 3.79-3.66 (m, 2H), 2.79 (d, J=8.91 Hz, 1H), 1.14-1.05 (m, 1H),0.67-0.59 (m, 1H), 0.43-0.29 (m, 2H), 0.22-0.15 (m, 1H). LCMS (Method 2)m/z 273.2 (M+H)⁺.

Intermediate c: Enantiomer A of1-cyclopropyl-1-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)methanamine

Enantiomer A of 4-chlorophenyl(cyclopropyl)methanamine (purified fromthe racemate of 4-chlorophenyl(cyclopropyl)methanamine by preparativeHPLC using a Chiralpak AYH 250×20 mm column (Daicel) (eluent EtOH DEA0.1% v/v, flow 10 ml min, 427 mg, 2.35 mmol) andpyridine-2-carboxaldehyde (201 mg, 1.87 mmol), were reacted according toGeneral Procedure A to afford the titled compound (433 mg, 85%) as ayellow oil. ¹HNMR (CDCl₃) δ 8.56 (d, J=4.5 Hz, 1H), 7.63-7.57 (m, 1H),7.35-7.28 (m, 4H), 7.17-7.12 (m, 2H), 3.77-3.66 (m, 2H), 2.79 (d, J=9.0Hz, 1H), 2.38 (bs, 1H), 1.13-1.03 (m, 1H), 0.67-0.58 (m, 1H), 0.43-0.28(m, 2H), 0.21-0.14 (m, 1H). MS (ES⁺) m/z 273.2 (M+H⁺).

Intermediate d: Enantiomer B of1-cyclopropyl-1-(4-chlorophenyl)-N-(pyridin-2-ylmethyl)methanamine

Enantiomer B of 4-chlorophenyl(cyclopropyl)methanamine (purified fromthe racemate of 4-chlorophenyl(cyclopropyl)methanamine by preparativeHPLC using a Chiralpak AYH 250×20 mm column (Daicel) (eluent EtOH DEA0.1% v/v, flow 10 ml min, 419 mg, 2.31 mmol) andpyridine-2-carboxaldehyde (201 mg, 1.87 mmol), were reacted according toGeneral Procedure A to give the titled compound (499 mg, 98%) as ayellow oil. ¹HNMR (CDCl₃) δ 8.56 (d, J=4.5 Hz, 1H), 7.63-7.57 (m, 1H),7.35-7.28 (m, 4H), 7.17-7.12 (m, 2H), 3.77-3.66 (m, 2H), 2.79 (d, J=9.0Hz, 1H), 2.38 (bs, 1H), 1.13-1.03 (m, 1H), 0.67-0.58 (m, 1H), 0.43-0.28(m, 2H), 0.21-0.14 (m, 1H). MS (ES⁺) m/z 273.2 (M+H⁺).

Intermediate i 1-cyclopentyl-1-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)methanamine

Cyclopentyl(4-fluorophenyl)methanamine hydrochloride (200 mg, 0.87 mmol)and 2-pyridinecarboxaldehyde (93 mg, 0.87 mmol) were reacted accordingto General Procedure A (however triethylamine (0.12 mL, 0.87 mmol) wasstirred for 10 min with the amine hydrochloride prior to addition ofaldehyde) to give the title compound as a yellow oil (251 mg,quantitative). ¹H NMR (CDCl₃) δ 8.58-8.56 (m, 1H), 7.61 (td, J=7.7, 1.8Hz, 1H), 7.33-7.25 (m, 2H), 7.17-6.99 (m, 4H), 3.69 (d, J=14.2 Hz, 1H),3.59 (d, J=14.2 Hz, 1H), 3.32 (d, J=8.3 Hz, 1H), 2.18-1.22 (m, 8H),1.10-1.01 (m, 1H). HPLC (Method 1) Rt 2.72 min (Purity: 95.1%). UPLC/MS(Method 3) 285.2 (M+H)⁺.

Intermediate l1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-N-(pyridin-2-ylmethyl)propan-1-amine

1-(2-Methyl-2,3-dihydro-benzofuran-5-yl)-propylamine (178 mg, 0.93 mmol)and 2-pyridinecarboxaldehyde (100 mg, 0.93 mmol), were reacted accordingto General Procedure A to give the title compound as a yellow oil (190mg, 72%). ¹H NMR (d₆-DMSO) δ 8.46-8.44 (m, 1H), 7.75-7.69 (m, 1H),7.40-7.38 (m, 1H), 7.23-7.19 (m, 1H), 7.13 (s, 1H), 6.98-6.96 (m, 1H),6.65-6.62 (m, 1H), 4.93-4.82 (m, 1H), 3.63-3.51 (m, 2H), 3.30-3.24 (m,1H), 2.80-2.71 (m, 1H), 2.64-2.52 (m, 1H), 1.74-1.65 (m, 1H), 1.55-1.46(m, 1H), 1.39-1.37 (d, J=6.2 Hz, 3H), 0.77-0.72 (t, J=7.4 Hz, 3H). HPLC(Method 1) Rt 7.76 min (Purity: 99.4%). UPLC/MS (Method 3) 283.1 (M+H)⁺.

Intermediate v1-(2,3-dihydro-1H-inden-5-yl)-N-[2-(3,6-dimethylpyrazin-2-yloxy)ethyl]ethanamine

1-Indan-5-yl-ethylamine (107 mg, 0.66 mmol) and intermediate mm (110 mg,0.73 mmol), were reacted according to General Procedure A to give thetitle compound as clear oil. ¹H NMR (CDCl₃) δ 7.83 (s, 1H), 7.20-7.07(m, 3H), 4.44-7.32 (m, 2H), 3.82 (q, J=6.6 Hz, 1H), 2.96-2.82 (m, 6H),2.42 (s, 3H), 2.36 (s, 3H), 2.12-2.02 (m, 2H), 1.37 (d, J=6.6 Hz, 3H).-LCMS (Method 2) m/z 312.5 (M+H)⁺.

Intermediate x1-(2,3-dihydro-1H-inden-5-yl)-N-[2-(6-chloropyridin-2-yloxy)ethyl]ethanamine

5-Acetylindane (106 mg, 0.66 mmol) and intermediate kk were reacted asdescribed according to General Procedure A to afford the titled compoundas a yellow oil. ¹HNMR (CDCl₃) δ 7.51 (t, J=7.8 Hz, 1H), 7.21-7.08 (m,3H), 6.88 (d, J=7.8 Hz, 1H), 6.65 (d, J=7.8 Hz, 1H), 4.43-4.31 (m, 2H),3.82 (q, J=6.6 Hz, 1H), 2.94-2.79 (m, 6H), 2.12-2.02 (m, 2H), 1.76 (s,1H), 1.37 (d, J=6.6 Hz, 3H). LCMS (Method 2) m/z 317.3 (M+H)⁺.

Intermediate y1-(2,3-dihydro-1H-inden-5-yl)-N-[2-(pyridin-2-yloxy)ethyl]ethanamine

5-Acetylindane (214 mg, 1.34 mmol) and 2-(pyridin-2-yloxy)ethanamine(prepared according to the procedure outlined in Tetrahedron 1988,44(1), 91-100) (448 mg, 3.24 mmol), were reacted as described accordingto General Procedure A to afford the titled compound (275 mg, 73%) as ayellow oil. ¹HNMR (CDCl₃) δ 8.14-8.12 (m, 1H), 7.58-7.53 (m, 1H),7.22-7.08 (m, 3H), 6.87-6.83 (m, 1H), 6.75-6.72 (m, 1H), 4.43-4.30 (m,2H), 3.82 (q, J=6.6 Hz, 1H), 2.95-2.80 (m, 6H), 2.12-2.02 (m, 2H), 1.76(s, 1H), 1.37 (d, J=6.6 Hz, 3H). LCMS (Method 2) m/z 283.3 (M+H)⁺.

Intermediate bb1-(2,3-dihydro-1H-inden-5-yl)-N-[2-(6-methylpyridin-2-yloxy)ethyl]ethanamine

5-Acetylindane (214 mg, 1.34 mmol) and2-[(6-methylpyridin-2-yl)oxy]ethanamine (prepared according to theprocedure outlined in U.S. Pat. No. 3,535,328 (A), 761 mg, 5.0 mmol),were reacted as described according to General Procedure A to afford thetitled compound as a yellow oil. ¹HNMR (CDCl₃) δ 7.44 (dd, J=8.1, 7.2Hz, 1H), 7.22-7.08 (m, 3H), 6.70 (d, J=7.2 Hz, 1H), 6.52 (d, J=8.1 Hz,1H), 4.41-4.28 (m, 2H), 3.82 (q, J=6.6 Hz, 1H), 2.94-2.79 (m, 6H), 2.42(s, 3H), 2.12-2.02 (m, 2H), 1.88 (s, 1H), 1.37 (d, J=6.6 Hz, 3H). LCMS(Method 2) m/z 297.2 (M+H)⁺.

Intermediate cc1-(2,2-dimethyl-1,3-benzoxathiol-5-yl)-N-(pyridin-2-ylmethyl)ethanamine

1-(2,2-Dimethyl-1,3-benzoxathiol-5-yl)ethanone (prepared according toprocedure outlined in the Journal of Heterocyclic Chemistry, 1984,21(2), 573-6 and 1982, 19(1), 135-9) (126 mg; 0.60 mmol),2-(aminomethyl)pyridine (262 mg, 2.42 mmol) and p-toluenesulfonic acidmonohydrate (12 mg, 0.06 mmol) were reacted according to GeneralProcedure B, to give the title compound as a pale yellow oil (156 mg,86%). ¹H NMR (CDCl₃) δ 8.54 (ddd, J=4.9, 1.7, 0.9 Hz, 1H), 7.60 (td,J=7.7, 1.7 Hz, 1H), 7.21-7.13 (m, 3H), 6.95 (dd, J=8.2, 1.9 Hz, 1H),6.69 (d, J=8.2 Hz, 1H), 3.82-3.71 (m, 3H), 2.47 (brs, 1H), 1.84 (s, 6H),1.39 (d, J=6.6 Hz, 3H). HPLC (Method 1) Rt 2.84 min (Purity: 98.6%).UPLC/MS (Method 3) 301.1 (M+H)⁺.

Intermediate dd:(1S)-1-(2-methoxyphenyl)-N-(pyridin-2-ylmethyl)ethanamine

2-Pyridinecarboxaldehyde (200 mg, 1.87 mmol) and(S)-2-methoxy-α-methylbenzylamine (282 mg, 1.87 mmol), were reactedaccording to General Procedure A to give the title compound as a yellowoil (368 mg, 81%). ¹H NMR (CDCl₃) δ 8.54 (m, 1H), 7.60 (td, J=7.7, 1.8Hz, 1H), 7.41 (dd, J=7.5, 1.6 Hz, 1H), 7.26-7.19 (m, 2H), 7.12 (m, 1H),6.96 (m, 1H), 6.87 (d, J=8.2 Hz, 1H), 4.24 (q, J=6.7 Hz, 1H), 3.82 (s,3H), 3.78 (s, 2H), 2.33 (brs, 1H), 1.42 (d, J=6.7 Hz, 3H). HPLC(Method 1) Rt 2.11 min (Purity: 99.1%). UPLC/MS (Method 3) 243.0 (M+H)⁺.

Intermediate ee:(1R)-1-(2-methoxyphenyl)-N-(pyridin-2-ylmethyl)ethanamine

2-Pyridinecarboxaldehyde (200 mg, 1.87 mmol) and(R)-2-methoxy-α-methylbenzylamine (282 mg, 1.87 mmol) were reactedaccording to General Procedure A to give the title compound as a yellowoil (368 mg, 81%). ¹H NMR (CDCl₃) δ 8.54 (ddd, J=4.9, 1.6, 0.8 Hz, 1H),7.60 (td, J=7.7, 1.8 Hz, 1H), 7.42 (dd, J=7.5, 1.7 Hz, 1H), 7.26-7.19(m, 2H), 7.12 (m, 1H), 6.96 (td, J=7.4, 1.0 Hz, 1H), 6.86 (dd, J=8.2,0.8 Hz, 1H), 4.22 (q, J=6.6 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 2H), 2.33(brs, 1H), 1.41 (d, J=6.6 Hz, 3H). HPLC (Method 1) Rt 2.05 min (Purity:98.8%). UPLC/MS (Method 3) 243.1 (M+H)⁺.

Intermediate ff:1-[2-(methoxymethyl)phenyl]-N-(pyridin-2-ylmethyl)ethanamine

1-[2-(Methoxymethyl)phenyl]ethanone (prepared according to procedureoutlined in the Journal of Organic Chemistry, 1970, 35(8), 2532-8) (205mg, 1.25 mmol), 2-(aminomethyl)pyridine (135 mg, 1.25 mmol) andp-toluenesulfonic acid monohydrate (24 mg, 0.12 mmol), were reactedaccording to General Procedure B to give the title compound as a yellowoil (276 mg, 86%). ¹H NMR (CDCl₃) δ 8.58-8.52 (m, 1H), 7.66 (d, J=7.8,1H), 7.61 (td, J=7.7, 1.8, 1H), 7.39-7.28 (m, 2H), 7.19 (ddd, J=12.4,8.2, 3.1, 3H), 4.45 (s, 2H), 4.24 (q, J=6.5, 1H), 3.78 (s, 2H), 3.33 (s,3H), 1.44 (d, J=6.5, 3H). HPLC (Method 1) Rt 2.34 min (Purity: 96.2%).UPLC/MS (Method 3) 257.1 (M+H)⁺.

Intermediate qq:1-(2,3-dihydro-1H-inden-5-yl)-N-(pyridin-2-ylmethyl)ethanamine

5-Acetylindane (1.0 g, 6.24 mmol) and 2-(aminomethyl)pyridine (639 μl,6.24 mmol) were reacted according to General Procedure B to give thetitle compound as a yellow oil. ¹H NMR (d₆-DMSO) δ 8.47-8.45 (m, 1H),7.76-7.70 (m, 1H), 7.41-7.39 (m, 1H), 7.24-7.06 (m, 4H), 3.71-3.65 (m,1H), 3.59 (s, 2H), 2.85-2.79 (m, 4H), 2.02-1.98 (m, 2H), 1.26 (d, J=6.6Hz, 3H). HPLC (Method 1) Rt 2.39 min (Purity: 91.7%). UPLC/MS (Method 3)253.1 (M+H)⁺.

Intermediate hh: 3-(4-Fluorophenyl)butanal

3-(4-Fluorophenyl)butan-1-ol (2.01 g, 11.94 mmol), oxalyl chloride (1.60mL, 18.34 mmol), DMSO (2.60 mL, 36.61 mmol) and TEA (10.00 mL, 74.46mmol), were reacted according to General Procedure G to afford thetitled compound (1.69 g, 85%) as a yellow oil. ¹HNMR (CDCl₃) δ 9.69 (t,J=1.8 Hz, 1H), 7.21-7.14 (m, 2H), 7.02-6.95 (m, 2H), 3.36 (sextet, J=7.2Hz, 1H), 2.77-2.60 (m, 2H), 1.29 (d, J=7.2 Hz, 3H).

Intermediate kk: 2-[(6-chloropyridin-2-yl)oxy]lethanamine

To a solution of ethanolamine (1.00 g, 16.4 mmol) in anhydrous1,4-dioxane (20 mL) at RT was added NaH (60% in oil) (655 mg, 16.4 mmol)portion-wise. The reaction mixture was heated to reflux (100° C.) for 30mins, then cooled to RT and 2,6-dichloropyridine (2.423 g, 16.4 mmol)was then added. The reaction mixture was again heated to reflux (100°C.) for 3 hr, then cooled to RT, quenched with water and extracted withdiethyl ether. The combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure to afford crude2-[(6-chloropyridin-2-yl)oxy]ethanamine which was purified by flashchromatography eluting initially with 1:1 EtOAc:hexane to remove anyremaining 2,6-dichloropyridine then eluted with 1:9 MeOH:DCM to obtainpure 2-[(6-chloropyridin-2-yl)oxy]ethanamine as a pale yellow oil (1.846g, 65% yield). ¹H NMR (CDCl₃) δ 7.50 (t, J=7.8 Hz, 1H), 6.88 (d, J=7.8Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 4.31 (t, J=5.4 Hz, 2H), 3.05 (t, J=5.4Hz, 2H), 1.35 (br s, 2H).

Intermediate ll: 2-[(3,6-dimethylpyrazin-2-yl)oxy]ethanol

To a solution of ethylene glycol (1.00 g, 16.11 mmol) in anhydrous DMF(10 mL) at RT was added NaH (60% in oil) (222 mg, 6.04 mmol)portion-wise. The reaction mixture was stirred for 5 min before additionof 3-chloro-2,5-dimethylpyrazine (574 mg, 4.03 mmol). The mixture washeated to 50° C. for 20 hr, then cooled to RT, quenched with water andextracted with. The combined organic extracts were dried (MgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash chromatography eluting with 1:4 EtOAc:hexane to affordthe titled compound as a pale yellow solid. ¹H NMR (CDCl₃) δ 7.87 (s,1H), 4.50-4.47 (m, 2H), 3.98-3.93 (m, 2H), 3.44 (t, J=5.7 Hz, 1H), 2.42(s, 3H), 2.38 (s, 3H). LCMS (Method 2) m/z 169.3 (M+H)⁺.

Intermediate mm: [(3,6-dimethylpyrazin-2-yl)oxy]acetaldehyde

Intermediate ll (150 mg, 0.89 mmol) was reacted according to GeneralProcedure G and the crude aldehyde was used as such without furtherpurification. LCMS (Method 2) m/z 167.3 (M+H)⁺.

Intermediate nn: 3-(4-fluorophenyl)butanoyl chloride

3-(4-Fluorophenyl)butanoic acid (2 g, 9.97 mmol) and thionyl chloride(20 mL) were reacted according to General Procedure J to afford thetitled compound (quantitative conversion) as a clear oil, which was usedwithout further purification.

Intermediate qq: 2-(4-fluorophenyl)cyclopropanecarbonyl chloride

2-(4-fluorophenyl)cyclopropanecarboxylic acid (2 g, 10.07 mmol) andthionyl chloride (20 mL) were reacted according to General Procedure Jto afford the titled compound as a clear oil, which was used withoutfurther purification.

Intermediate uu:cyclopropyl(2,2-dimethyl-1,3-benzoxathiol-5-yl)methanone

To a solution of cyclopropancarbonyl chloride (2.6 g, 25.26 mmol) inanhydrous DCM (20 mL) at −10° C. under a nitrogen atmosphere was addedAlCl₃ (1.7 g, 12.63 mmol) portion-wise and the mixture was stirred untilhomogeneous. The solution was then added to a solution of2,2-dimethyl-1,3-benzoxathiole (prepared according to procedure outlinedin the Journal of Heterocyclic Chemistry, 1984, 21 (2), 573-6 and 1982,19(1), 135-9) (2.1 g, 12.63 mmol) in anhydrous DCM (20 mL) at −10° C.After stirring for 30 min at −10° C., the mixture was poured into 5MNaOH. The aqueous phase was extracted twice with DCM. The combinedorganics were dried (MgSO₄), filtered and concentrated under reducedpressure to give an oil. The oil was purified by column chromatographyusing 5% to 20% EtOAc in n-heptane to give title compound as a whitesolid (542 mg, 18%). ¹H NMR (CDCl₃) δ 7.80 (d, J=1.9 Hz, 1H), 7.74 (dd,J=8.3, 1.9 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 2.60-2.53 (m, 1H), 1.86 (s,6H), 1.22-1.17 (m, 2H), 1.02-0.96 (m, 2H). HPLC (Method 1) Rt 4.15 min(Purity: 86.9%).

Intermediate vvcyclopropyl(2,2-dimethyl-3.3-dioxido-1,3-benzoxathiol-5-yl)methanone

To a solution of Intermediate uu (542 mg, 2.31 mmol) in glacial AcOH (10mL) at 0° C. was added H₂O₂ (2.62 mL, 23.13 mmol). After stirring for 30min at RT, H₂O₂ (5.2 mL, 46.26 mmol) was added and the reaction wasstirred at RT for 18 hr. DCM was added and the organic phase was washedwith water, 1N NaOH, saturated solution of sodium thiosulfate, dried(MgSO₄), filtered and concentrated under reduced pressure to give thetitle compound as a white solid (625 mg, quantitative). ¹H NMR (CDCl₃) δ8.04 (d, J=1.9 Hz, 1H), 7.89 (dd, J=8.7, 1.9 Hz, 1H), 6.76 (d, J=8.7 Hz,1H), 2.30-2.22 (m, 1H), 1.44 (s, 6H), 0.95-0.90 (m, 2H), 0.78-0.72 (m,2H). HPLC (max plot) 93.7%; Rt 3.40 min. UPLC/MS (Method 3) 267.0(M+H)⁺.

Intermediate ww(E)-cyclopropyl(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-5-yl)methanoneoxime

A solution of Intermediate vv (625 mg, 2.35 mmol) in hydroxylamine (10mL) and EtOH (10 mL) was heated at 90° C. for 2 days. The mixture wasthen cooled to RT, water was added and the mixture was extracted fourtimes with DCM. The combined organics were washed with water, dried(MgSO₄), filtered and concentrated under reduced pressure. n-Heptane wasadded and the solid was triturated, sonicated and filtered to give thetitle compound as a white solid (578 mg, 88%). UPLC/MS (Method 3) 282.0(M+H)⁺.

Intermediate xx1-cyclopropyl-1-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-5-yl)methanamine

A solution of Intermediate ww (578 mg, 2.05 mmol) in MeOH (20 mL) washydrogenated in H-Cube® (Thalesnano) with Raney nickel 1 mL/min 60 barsat 90° C. under recycling condition for 3 hr. The mixture was thenconcentrated under reduced pressure and the titled compound was isolatedas HCl salt (white solid) after exposure to HCl (1.25N in diethyl ether)(380 mg, 61%). HPLC (max plot) 90.5%; Rt 3.40 min. UPLC/MS (Method 3)251.0 (M+H)⁺.

Intermediate yy:1-cyclopropyl-1-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-5-yl)-N-(pyridin-2-ylmethyl)methanamine

Intermediate xx (195 mg, 0.64 mmol) and 2-pyridinecarboxaldehyde (69 mg;0.64 mmol) were reacted according to General Procedure A (howevertriethylamine (0.089 mL, 0.64 mmol) was stirred for 10 min with theamine hydrochloride prior to addition of aldehyde) to give the titlecompound as a yellow oil (180 mg, 78%). ¹H NMR (CDCl₃) δ 8.57-8.55 (m,1H), 7.79-7.62 (m, 3H), 7.19-6.99 (m, 3H), 3.89-3.70 (m, 2H), 2.88 (d,J=9.0 Hz, 1H), 1.75 (s, 6H), 1.19 (brs, 1H), 0.75-0.17 (m, 4H). HPLC(Method 1) Rt 2.26 min (Purity: 86.3%). UPLC/MS (Method 3) 359.1 (M+H)⁺.

Intermediate zz:1-(4-methyl-4H-1,2,4-triazol-3-yl)-N-(pyridin-2-ylmethyl)ethanamine

1-(4-Methyl-4H-[1,2,4]triazol-3-yl)-ethylamine dihydrochloride (140 mg;0.70 mmol) and 2-pyridinecarboxaldehyde (83 mg, 0.77 mmol) were reactedaccording to General Procedure A to give the title compound as an oil.UPLC/MS (Method 3) 218.1 (M+H)⁺.

Intermediate aaa:1-(3-ethyl-1,2,4-oxadiazol-5-yl)-N-(pyridin-2-ylmethyl)ethanamine

1-(3-ethyl-1,2,4-oxadiazol-5-yl)ethanamine (180 mg, 0.71 mmol) and2-pyridinecarboxaldehyde (83 mg, 0.78 mmol), were reacted according toGeneral Procedure A to give the title compound as an oil (87 mg, 53%).¹H NMR (de-DMSO) δ 8.56-8.54 (m, 1H), 7.64 (dt, J=1.8, 7.7 Hz, 1H),7.30-7.28 (m, 1H), 7.19-7.15 (m, 1H), 4.19 (q, J=6.9 Hz, 1H), 4.00-3.88(m, 2H), 3.10-2.70 (br s, 1H) 2.75 (q, J=7.6 Hz, 2H), 1.58 (d, J=6.9 Hz,3H), 1.32 (t, J=7.6 Hz, 3H). UPLC/MS (Method 3) 233.1 (M+H)⁺.

Intermediate ab: Enantiomer A of1-(4-fluorophenyl)-N-[2-(4-fluoropiperidin-1-yl)ethyl]-2-methylpropan-1-amine

Step 1: 2-chloro-N-[(1 S)-1-(4-fluorophenyl)-2-methylpropyl]acetamide

To a solution of intermediate bk (0.50 g, 167 mmol) in anhydrous DCM (10mL) at RT was added DIPEA (610 μL, 129 mmol)) followed by chloroacetylchloride (280 μL, 113 mmol. The reaction progress was monitored byLCMS and TLC, upon completion the reaction mixture was diluted withEtOAc and washed with NH₄Cl (1/2 sat. aq., 2×) and brine (lx), dried(Na₂SO₄) and concentrated under reduced pressure. The crude product waspurified by flash silica gel chromatograph (20% EtOAc/hexane, Rf=0.24)to give the intermediate shown as a white solid (94%, 683 mg). LCMS(Method 2) m/z 244.3 (M+H)⁺.

Step 2:N-[(1S)-1-(4-fluorophenyl)-2-methylpropyl]-2-(4-fluoropiperidin-1-yl)acetamide

A solution of the amide (332 mg, 243 mmol), NaI (620 mg, 150 mmol),Na₂CO₃ (296 mg, 106 mmol) and 4-fluoropiperidine.HCl (385 mg, 140 mmol)in anhydrous DMF was flushed with N₂, stoppered and heated to 60° C. ON.The reaction mixture was diluted with EtOAc and washed with NH₄Cl (1/2sat. aq., 3×) and brine (lx), dried (Na₂SO₄) and concentrated underreduced pressure. The crude product was purified by flash silica gelchromatography (60% EtOAc/hexane, Rf=0.34) to give the intermediateshown as a yellow oil (97%, 408 mg). LCMS (Method 2) m/z 311.2 (M+H)⁺.

Step 3: Enantiomer A of1-(4-fluorophenyl)-N-[2-(4-fluoropiperidin-1-yl)ethyl]-2-methylpropan-1-amine

To a 0° C. solution of the amide (389 mg, 310 mmol) in anhydrous THF (5mL) was added LiAlH₄ (133 mg, 351 mmol) and the reaction mixture warmedto 50° C. Reaction progress was monitored by LCMS and upon completionwas quenched by cooling to 0° C., diluting with EtOAc (10 mL) and slowaddition of NaK tartrate (1M) solution. A grey solid formed and thereaction mixture was for 3 days during which time the solids dissolved.The product was extracted into EtOAc (3×) and the pooled extracts weredried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct was purified by flash silica gel chromatography (4% MeOH/EtOAc,Rf=0.24) to give the title compound as a yellow oil (82%, 408 mg). LCMS(Method 2) m/z 297.2 (M+H)⁺.

Intermediate ac:Cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(2,2-difluoro-2-pyridin-2-yl-ethyl)-amine

Tetraethyl orthotitanate (2.84 mL, 13.4 mmol) was added into a solutionof cyclopropyl[3-(ethylsulfonyl)phenyl]methanone (2.0 g; 8.4 mmol) and2,2-difluoro-2-pyridin-2-yl-ethylamine benzenesulfonate (3.18 g, 10.1mmol) in anhydrous THF (16 mL) at RT. The resulting mixture was heatedat reflux for 2 hours, and then cooled to RT. Sodium borohydride (952mg, 25.2 mmol) was added and the resulting mixture was stirred at RTuntil completion. The reaction mixture was poured in MeOH (20 mL) undervigorous stirring, and then the resulting suspension was filtered offand rinsed with MTBE. A 1N aqueous solution of NaOH (100 mL) was addedto the filtrate under vigorous stirring and the precipitate was removedby filtration. The resulting biphasic filtrate was separated and theaqueous layer was extracted with MTBE. The combined organic layers werewashed with water and brine, dried (Na₂SO₄) and concentrated underreduced pressure. After purification by flash chromatography (silica,petroleum ether/EtOAc 1:1), the title compound was obtained as acolourless oil (790 mg, 25%). UPLC/MS (max plot) 90.3%; Rt 1.54 min;(MS+) 381.4 ([M+H]⁺).

Intermediate ad:N-[(4-chlorophenyl)(cyclopropyl)methyl]-8-methyl-8-azabicyclo[3.2.1]octan-3-amine

To a solution of 4-chlorobenzaldehyde (400 mg, 2.84 mmol) and8-methyl-8-azabicyclo[3.2.1]octan-3-amine (413 mg, 2.98 mmol) inanhydrous THF (6 mL) was added magnesium sulphate (685 mg, 5.69 mmol)and the resulting reaction mixture was stirred at RT for 4 hours.Reaction mixture was filtered and filtrate was concentrated underreduced pressure to obtain imine-intermediate as light brown oil (748mg). Cyclopropyl bromide (5.69 mmol) was dissolved in dry diethyl ether(6 mL) under nitrogen atmosphere at −78° C. and treated with tert-BuLi.After 10 minutes, cooling was removed and the mixture was stirred atroom temperature for 1 hr. Reaction mixture was again cooled to −78° C.and a solution of imine-intermediate in dry diethyl ether (4 mL) wasadded slowly. Cooling was removed and reaction was stirred at roomtemperature for 24 hr. The crude reaction mixture was diluted with EtOAcand the organics washed with ammonium chloride (aqueous) solutionfollowed by brine. The organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure to provide the title compound (800mg), which was used without purification to the next step. ¹H NMR(CDCl₃) δ 7.29-7.21 (m, 4H), 3.08-3.0 (m, 2H), 2.87 (d, J=8.4 Hz, 1H),2.67-2.61 (m, 1H), 2.23 (s, 3H), 2.03-1.38 (m, 9H), 1.02-0.88 (m, 1H),0.63-0.53 (m, 1H), 0.43-0.33 (m, 1H), 0.32-0.18 (m, 1H). MS (ES⁺) m/z305.2 (M+H⁺).

Intermediate ae: 1-(4-ethanesulfonyl-phenyl)-propylamine

Step 1: 1-(4-ethylsulfanyl-phenyl)-propan-1-one

Aluminium chloride (8.78 g, 65.8 mmol) was added into a solution ofpropionyl chloride (4.86 mL, 55.7 mmol) in anhydrous DCM (35 mL) cooledat 5° C. The resulting solution was stirred at 5° C. for 15 minutes, andthen added dropwise over 5 minutes into a solution of (ethylthio)benzenein anhydrous DCM (35 mL) cooled at −10° C. After 1.5 hours at −10° C.,the reaction mixture was poured into a mixture of a 5N aqueous solutionof HCl (100 mL) and crushed ice, and then was extracted with DCM (2×100mL). The combined organic layers were washed with a saturated solutionof NaHCO₃ and brine, then dried (MgSO₄) and concentrated under reducedpressure to give the title compound as a greenish solid (8.7 g, 88%),use without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 7.94-7.81(m, 2H), 7.45-7.34 (m, 2H), 3.04 (m, 4H), 1.28 (t, J=7.3 Hz, 3H), 1.07(t, J=7.2 Hz, 3H). UPLC/MS (max plot) 100%; Rt 1.78 min; (MS+) 195.1([M+H]⁺).

Step 2: 1-(4-ethanesulfonyl-phenyl)-propan-1-one

A solution of oxone monopersulfate (58.8 g, 94.0 mmol) in water (160 mL)was added over 5 minutes into a solution of1-(4-ethylsulfanyl-phenyl)-propan-1-one (8.7 g, 44.8 mmol) in EtOAc (80mL). The resulting mixture was stirred at RT for 4 hours under vigorousstirring. The layers were separated and the aqueous layer was extractedwith EtOAc (300 mL). The combined organic layers were washed with water(200 mL) and brine (200 mL), and then dried (MgSO₄) and concentratedunder reduced pressure to give 8.86 g of an off-white solid. The solidwas triturated in Et₂O, and then filtered off and dried under reducedpressure to give the title compound as a white solid (7.8 g, 77%). ¹HNMR (300 MHz, DMSO-d6) δ 8.29-8.11 (m, 2H), 8.11-7.95 (m, 2H), 3.38 (q,J=7.4 Hz, 2H), 3.13 (q, J=7.1 Hz, 2H), 1.19-1.01 (m, 6H). HPLC (maxplot) 99.7%; Rt 2.90 min. UPLC/MS (max plot) 100%; Rt 1.09 min; (MS+)244.3 ([M+NH₄]⁺).

Step 3: allyl-[1-(4-ethanesulfonyl-phenyl)-propyl]-amine

A solution of 1-(4-ethanesulfonyl-phenyl)-propan-1-one (5.80 g, 25.6mmol) and allylamine (3.85 mL, 51.3 mmol) was prepared in anhydrous THF(70 mL), and then tetraethyl orthotitanate (8.6 mL, 41.0 mmol) wasadded. The resulting mixture was heated at 60° C. for 2 hours, and thenstirred at RT for 15 hours. The reaction mixture was cooled down to 5°C. and NaBH₄ (1.94 g, 51.3 mmol) was added portion-wise over 5 min. Theresulting mixture was stirred for 2 hours allowing temperature to warmup to RT, and then MeOH (60 mL) was added drop-wise over 15 min. Themixture was diluted with a 1N aqueous solution of HCl (100 mL) andwashed twice with MTBE (2×50 mL). The aqueous layer was basified with a1N aqueous solution of NaOH and extracted with MTBE (2×100 mL). Theorganic layers were combined, washed with brine, dried (MgSO₄) andconcentrated under reduced pressure to give the title compound as acolourless oil (3.67 g, 54%), used without further purification. UPLC/MS(max plot) 98.3%; Rt 1.11 min; (MS+) 268.2 ([M+H]⁺).

Step 4: 1-(4-ethanesulfonyl-phenyl)-propylamine

A mixture of bis(dibenzylideneacetone)palladium (387 mg, 0.67 mmol) and14-bis(diphenylphosphino)butane (287 mg, 0.67 mmol) was prepared in THF(20 mL) under nitrogen and stirred at RT for 15 minutes. The preformedcatalyst and thiosalicylic acid (2.28 g, 14.8 mmol) were added into asolution of allyl-[1-(4-ethanesulfonyl-phenyl)-propyl]-amine (3.60 g,13.5 mmol) in THF (20 mL). The resulting mixture was stirred at 60° C.for 3 hours until completion. The reaction mixture was diluted a 1Naqueous solution of HCl, and then washed with EtOAc. The aqueous layerwas basified with a 1N aqueous solution of NaOH, and then extracted withEtOAc (3×100 mL). The organic layers were combined, dried (MgSO₄) andconcentrated under reduced pressure to give 2.55 g of a yellow oil.After purification by flash chromatography (silica, THF), the racemictitle compound was obtained as a pale yellow oil (2.1 g, 69%). Refer toTable 1 for separation of enantiomers.

Intermediate af: 1-(4-methanesulfonyl-phenyl)-propylamine

The title compound was prepared following procedures described forIntermediate ae (steps 1 to 4), but starting from (methylthio)benzene instep 1. After purification by flash chromatography (silica, THF), theracemic title compound was obtained as a pale yellow oil (3.65 g). Referto Table 1 for separation of enantiomers.

Intermediate aq: tert-Butyl3-[amino(4-fluorophenyl)methyl]azetidine-1-carboxylate

Step 1: tert-Butyl 3-(4-fluorobenzoyl)azetidine-1-carboxylate

To a solution of 1-Bromo-4-fluorobenzene (20 g, 0.0984 mol) in drytetrahydrofuran (200 mL) was added n-Butyl lithium (76.8 mL, 0.1229 mol,1.6 M solution in hexane) in drops at −78° C. under nitrogen and stirredat same temperature for 1 hr. To this reaction mixture, tert-Butyl3-{[methoxy (methyl) amino] carbonyl} azetidine-1-carboxylate (20 g,0.0819 mol) in tetrahydrofuran (75 mL) was added at −78° C. The reactionmixture was stirred for 1 hr at −78° C. The reaction mixture wasquenched with ice and extracted with ethyl acetate (2×100 mL) and driedover sodium sulphate. The solvent was evaporated and the residue waspurified by column chromatography by using silica gel (60-120 mesh)using pet ether and ethyl acetate (80:20) as an eluent to afford (23 g,95%) of the title compound as a pale brown liquid. TLC: Pet ether/Ethylacetate: (5/5), R_(f)=0.6; ¹H NMR (400 MHz, DMSO-d₆): δ 7.98-7.94 (m,2H), 7.39-7.34 (m, 2H), 4.41-4.34 (m, 1H), 4.12 (s, 2H), 3.95 (s, 2H),1.36 (s, 9H).

Step 2: tert-Butyl3-[(E)-(4-fluorophenyl)(hydroxyimino)methyl]azetidine-1-carboxylate

To a solution of tert-Butyl 3-(4-fluorobenzoyl) azetidine-1-carboxylate(14 g, 0.0501 mol) in a mixture of methanol (120 mL) and water (20 mL)was added sodium acetate (10.2 g, 0.1253 mol) followed by hydroxyl aminehydrochloride (6.9 g, 0.1002 mol) at RT. The reaction mixture wasstirred at RT for 12 hr. After completion of the reaction, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved with ethyl acetate (200 mL), washed with an aqueous solutionof sodium bicarbonate (10%, 100 mL), water (100 mL), brine solution (100mL) and dried over sodium sulphate. The solvent was evaporated and thecrude material was purified by column chromatography by using pet etherand ethyl acetate (50:50) as an eluent to afford (13 g, 88%) of thetitle compound as a white solid. TLC: Pet ether/Ethyl acetate: (7/3),R_(f)=0.2; ¹H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 7.41-7.38 (m,2H), 7.25-7.20 (m, 2H), 4.12-4.08 (t, J=8.2 Hz, 1H), 4.04-3.95 (m, 2H),3.82-3.76 (m, 2H), 1.37 (s, 9H).

Step 3: tert-Butyl3-[amino(4-fluorophenyl)methyl]azetidine-1-carboxylate

To a solution of tert-Butyl3-[(E)-(4-fluorophenyl)(hydroxyimino)methyl]azetidine-1-carboxylate (12g, 0.0407 mol) in methanol (300 mL) was added palladium on carbon (10%,3.6 g). This reaction mixture was hydrogenated under 20 Kg of pressureof Hydrogen for 12 hr at RT. The reaction mixture was filtered offcatalyst and the filtrate was concentrated. The resulted residue waspurified by acid-base work up [the residue was taken in an aqueoussolution of citric acid (10%, 50 mL) and washed with ethyl acetate(2×100 mL). The separated aqueous layer was basified with an aqueoussolution of sodium bicarbonate (10%, 40 mL) and extracted with DCM(2×100 mL). The DCM layer was washed with brine solution, dried oversodium sulphate and evaporated under reduced pressure] to afford (8.5 g,74%) of the title compound as a white solid. TLC: Pet ether/Ethylacetate: (1/1), R_(f)=0.2; ¹H NMR (400 MHz, DMSO-d6): δ 7.39-7.36 (m,2H), 7.12-7.08 (m, 2H), 3.87-3.85 (d, J=8.9 Hz, 1H), 3.81-3.79 (d, J=5.9Hz, 2H), 3.57 (s, 1H), 3.46-3.43 (t, J=7.6 Hz, 1H), 2.67-2.50 (m, 1H),2.02 (s, 2H) 1.36 (s, 9H); LCMS: 181 [M−100]+

Intermediate ah:tert-butyl-3-{amino[4-(difluoromethoxy)phenyl]methyl}azetidine

Step 1: 3-(4-Benzyloxy-benzoyl)-azetidine-1-carboxylic acid tert-butylester

To a stirred solution of 1-(Benzyloxy)-4-bromobenzene (32.3 g, 0.12 mol)in dry THF (250 mL) was added n-Butyl lithium (83 mL, 0.13 mol, 1.6 Msolution in hexane) in drops at −78° C. under nitrogen and the reactionmixture was stirred at same temperature for 1 hr. To this reactionmixture, a solution of tert-butyl3-{[methoxy(methyl)amino]carbonyl}azetidine-1-carboxylate (25 g, 0.10mol) in dry THF (150 mL) was added in drops. The reaction mixture wasstirred at −78° C. for 1 hr. After completion of reaction, the reactionmixture was quenched with ice water and extracted with ethyl acetate(2×200 mL). The combined organic layer washed with water (200 mL), brine(100 mL) and dried over sodium sulphate. The solvent was concentratedunder reduced pressure; the crude product was slurred with pet ether(100 mL) and ethyl acetate (50 mL). The solids were filtered to afford(30 g, 75%) of the titled compound as white solid. TLC-Pet ether/Ethylacetate (8:2), R_(f)=0.7; ¹H NMR (400 MHz, DMSO-d₆) δ 7.84-7.82 (t,J=8.0 Hz, 2H), 7.46-7.31 (m, 5H), 7.14-7.10 (m, 2H), 5.20 (s, 2H),4.35-4.28 (m, 1H), 4.10 (s, 2H), 3.93 (s, 2H), 1.36 (s, 9H).

Step 2: tert-butyl3-[hydroxy(4-hydroxyphenyl)methyl]azetidine-1-carboxylate

To a solution 3-(4-benzyloxy-benzoyl)-azetidine-1-carboxylic acidtert-butyl ester (48 g, 0.01 mol) in methanol (600 mL) was added 10%Pd/C (5 g) and the reaction mixture was hydrogenated at 5.0 kg/cm⁻¹pressure of hydrogen at RT for 8 hr. After the completion of reaction,the reaction mixture was filtered through celite bed to remove thecatalyst and the filtrate was concentrated under reduced pressure. Thecrude product was purified by column chromatography by using pet etherand ethyl acetate as an eluent to afford (40 g, 98%) of the titledcompound as white solid. TLC-Pet ether/Ethyl acetate (5:5), R_(f)=0.5;¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 7.11-7.08 (m, 2H), 6.69-6.66(m, 2H), 5.31-5.30 (d, J=4.0 Hz, 1H), 4.50-4.47 (dd, J=4.0 Hz, 8.0 Hz,1H), 3.74 (s, 2H), 3.62 (s, 1H), 3.54-3.50 (t, J=16.0 Hz, 1H), 2.69-2.64(m, 1H), 1.39 (s, 9H).

Step 3: tert-butyl3-[[4-(difluoromethoxy)phenyl](hydroxy)methyl]azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-[hydroxy (4-hydroxyphenyl) methyl]azetidine-1-carboxylate (40 g, 0.143 mol) in a mixture of acetonitrile(400 mL) and potassium hydroxide (in water 400 mL) (160 g, 0.91 mol) ina 1 Ltr pressure vessel, was added diethyl(bromodifluromethyl)phosphonate (84 g, 0.09 mol) at −78° C. under nitrogen. The vessel wassealed and mixture was warmed to RT over a period of 30 min. Aftercompletion of reaction, mixture was diluted with diethyl ether (400 mL)and stirred for 15 min. The organic layer separated and washed withwater (200 mL), brine (100 mL) and dried over sodium sulphate. Thesolvent was concentrated under reduced pressure. The crude product waspurified by column chromatography by using pet. ether and ethyl acetateas an eluent to afford (22 g, 50%) of the titled compound as whitesolid. TLC-Pet ether/Ethyl acetate (5:5), R_(f)=0.3; ¹H NMR (400 MHz,DMSO-d₆) δ 7.39-7.00 (m, 5H), 5.56 (s, 1H), 4.65-4.62 (dd, J=4.0 Hz, 12Hz, 1H), 3.76-3.61 (m, 4H), 2.74-2.70 (t, J=16 Hz, 1H), 1.36 (s, 9H).

Step 4: tert-butyl 3-[4-(difluoromethoxy)benzoyl]azetidine-1-carboxylate

To a stirred solution of oxalyl chloride (24.2 g, 0.19 mol) in DCM (200mL) was added DMSO (29.9 g, 0.38 mol) in drops at −78° C. undernitrogen. After 15 min, a solution of tert-butyl3-[[4-(difluoromethoxy)phenyl](hydroxy)methyl]azetidine-1-carboxylate(21 g, 0.06 mol) in DCM was added in drops at −78° C. The reactionmixture was stirred at same temperature for 3 hr. and was addedtriethylamine (54 mL, 0.38 mol) at −78° C. in drops. The reactionmixture was stirred for additional 2 hr. and quenched with aqueoussolution of sodium bicarbonate solution (10%, 200 mL) and extracted withDCM (2×200 mL). The combined organic layer was washed with aqueoussolution of citric acid (1%, 200 mL), water (200 mL), brine (100 mL) anddried over sodium sulphate. The solvent was concentrated under reducedpressure to afford (20 g, 96%) of the titled compound as white solid.TLC-Pet ether/Ethyl acetate (4:6), R_(f)=0.2; ¹H NMR (400 MHz, DMSO-d₆)δ 7.84-7.82 (t, J=8.0 Hz, 2H), 7.46-7.31 (m, 5H), 7.14-7.10 (m, 2H),5.20 (s, 2H), 4.35-4.28 (m, 1H), 4.10 (s, 2H), 4.39 (s, 2H), 1.36 (s,9H).

Step 5: tert-butyl3-[[4-(difluoromethoxy)phenyl](hydroxyimino)methyl]azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-[4-(difluoromethoxy) benzoyl]azetidine-1-carboxylate (20 g, 0.06 mol) in methanol (150 mL) and water(50 mL) was added sodium acetate (12.5 g, 0.15 mol) followed by hydroxylamine hydrochloride (8.4 g, 0.12 mol) at RT. The reaction mixture wasstirred at RT for 12 hr. The reaction mixture was concentrated underreduced pressure and the residue was diluted ethyl acetate (2×200 mL)was washed with aqueous sodium bicarbonate solution (10%, 200 mL), water(100 mL), brine (100 mL) and dried over sodium sulphate. The solvent wasconcentrated under reduced pressure to afford (20 g, 96%) of the titledcompound as an off white solid. TLC-Pet ether/Ethyl acetate (5:5),R_(f)=0.3; ¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 7.54-7.09 (m, 5H),4.11-3.76 (m, 5H), 1.34 (s, 9H).

Step 6: tert-butyl3-{amino[4-(difluoromethoxy)phenyl]methyl}azetidine-1-carboxylate

To a solution of tert-butyl3-[(Z)-[4-(difluoromethoxy)phenyl](hydroxyimino)methyl]azetidine-1-carboxylate(20 g, 0.05 mol) in methanol (500 mL) was added 10% Pd/C (3 g) and thereaction mixture was hydrogenated under 20 bar pressure of hydrogen atRT for 48 hr. The reaction mixture was filtered through celite bed toremove the catalyst and the filtrate was concentrated under reducedpressure to afford (16 g, 86%) of the titled compound as colourlessliquid. TLC-Pet ether/Ethyl acetate (4:6), R_(f)=0.2; ¹H NMR (400 MHz,DMSO-d₆) δ 7.34-6.99 (m, 5H), 3.87-3.85 (d, J=8.0 Hz, 3H), 3.79 (s, 1H),3.57-3.44 (m, 1H), 2.65-2.59 (m, 1H), 2.06-2.03 (d, J=12.0 Hz, 2H), 1.34(s, 9H); LCMS: (Method 1) 282.5 [M+100]⁺

Refer to Table 1 for separation of enantiomers.

Intermediate ai: tert-butyl4-(amino(4-(difluoromethoxy)phenyl)methyl)piperidine-1-carboxylate andIntermediate as: tert-Butyl 4-[4-(difluoromethoxy)benzoyl]piperidine-1-carboxylate

The title compounds were prepared following the procedures described forIntermediate ah (steps 1-6), but 1-(Benzyloxy)-4-bromobenzene (23 g,0.08 mol) and tert-butyl 4-{[methoxy (methyl) amino] carbonyl}piperidine-1-carboxylate (20 g, 0.07 mol) were used in Step 1.

Intermediate as (Step 4) was achieved as a white solid. TLC-Petether/Ethyl acetate (4:6), R_(f)=0.2; ¹H NMR (400 MHz, DMSO-d₆) δ 7.80(s, 1H), 7.71-7.00 (d, J=4.0 Hz, 1H), 7.66-7.64 (d, J=8.0 Hz, 1H),7.59-7.57 (t, J=16.0 Hz, 1H), 3.95-3.85 (m, 2H), 3.71-3.22 (m, 1H),3.28-3.22 (m, 2H) 2.53-2.48 (m, 2H), 2.03-1.99 (m, 2H), 1.74-1.71 (m,1H), 1.59-1.53 (m, 1H), 1.35 (bs, 9H), 1.22-1.19 (m, 1H), 1.09-0.99 (m,3H), 0.97-0.96 (m, 1H).

Intermediate ai (Step 6) was achieved as a colourless liquid. TLC-Petether/Ethyl acetate (4:6), R_(f)=0.2; ¹H NMR (400 MHz, DMSO-d₆) δ7.34-6.99 (m, 5H), 3.95-3.92 (d, J=12.0 Hz, 1H), 3.87-3.84 (d, J=12.0Hz, 1H), 3.55-3.53 (d, J=8.0 Hz, 1H), 2.59-2.48 (m, 2H), 1.97 (s, 1H),1.78-1.75 (d, J=12.0 Hz, 2H) 1.51-1.46 (m, 1H), 1.35 (s, 9H), 1.21-1.16(m, 1H), 1.04-0.89 (m, 2H). LCMS (Method 1) 254.4 (M−100)

Intermediate aj: {1-[4-(difluoromethoxy)phenyl]-2-methylpropyl} amine

Step-1: 1-[4-(difluoromethoxy) phenyl]-2-methylpropan-1-ol

To a stirred solution of 4-difluoromethoxy benzaldehyde (23 g, 0.1334mol) in dry THF (400 mL) under N₂, was added isopropyl magnesiumchloride (2.0 M in THF) (20.59 g, 100.1 mL, 0.2002 mol) slowly at 00° C.The reaction mixture was stirred at RT for 3 hr. TLC confirmed thecompletion of the reaction mixture. The reaction mixture was againcooled to 00° C. and quenched with saturated NH₄Cl solution andextracted with (2×1000 mL) of ethyl acetate. The organic layer wasseparated, dried over Na₂SO₄ and evaporated. The crude was passedthrough silica gel column (60-120 mesh), pet ether/ethyl acetate aselutent to afford (13 g, 45%) of the titled compound as pale yellowliquid. TLC-pet ether/ethyl acetate: (8/2): R_(f)=0.5; ¹H NMR (DMSO-d₆,400 MHz) δ 7.31-7.29 (d, J−11.2 Hz, 2H), 7.37-7.00 (t, 1H), 7.10-7.08(d, J−8.6 Hz, 2H), 5.13-5.12 (d, J−4.4 Hz, 1H), 4.25-4.22 (t, 1H),1.79-1.746 (m, 1H), 0.94-0.84 (d, 3H), 0.81-0.71 (d, 3H).

Step-2: 1-(1-azido-2-methylpropyl)-4-(difluoromethoxy)benzene

To an ice-cooled solution of 1-[4-(difluoromethoxy)phenyl]-2-methylpropan-1-ol (6.75 g, 0.0312 mol) in 21 mL of 56%sulphuric acid and 21 mL of chloroform was added sodium azide (6.1 g,0.0937 mol) in portions at 00° C. and the mixture was stirred at RT for5 hr. The reaction was completed by TLC. The reaction mixture wasdiluted with ice cold water (75 mL) and extracted with DCM (2×75 mL).The separated organic layer was washed with brine solution and driedover Na₂SO₄ and evaporated. The crude was passed through chromatographyusing silica gel (60-120 mesh) using pet ether/ethyl acetate as anelutent to afford (5.9 g, 79%) of the titled compound as pale yellowoil. TLC-pet ether/ethyl acetate: (8/2): R_(f)=0.7; LCMS (Method 1)214.3 (M−27) ¹H NMR (DMSO-d₆, 400 MHz) δ 7.39-7.37 (d, J−8.6 Hz, 2H),7.44-7.07 (t, 1H), 7.21-7.18 (d, J−8.6 Hz, 2H), 4.46-4.44 (d, J−8.2 Hz,1H), 1.97-1.92 (m, 1H), 0.95-0.93 (d, 3H), 0.81-0.70 (d, 3H).

Step-3: {1-[4-(difluoromethoxy) phenyl]-2-methylpropyl} amine

To a stirred solution of 1-(1-azido-2-methylpropyl)-4-(difluoromethoxy)benzene (20 g) in methanol (500 mL) was added 10% Pd on carbon (2.0 g)under N₂ bubbling. The reaction was carried out at 5 kg/cm² pressure ofH₂ at RT for 12 hr. The catalyst was collected by filtration and washedwith methanol. The combined filtrate concentrated under reducedpressure. The resulted residue was purified by acid-base work up. ie;The reaction mixture was taken with 10% citric acid solution and washedwith ethyl acetate (2×75 mL). The separated aqueous layer was basifiedwith 25% ammonia solution and extracted with ethyl acetate (2×50 mL),washed with brine, dried over Na₂SO₄ and evaporated under reducedpressure to afford (15 g, 84%) of the titled compound as a yellowliquid. Refer to Table 1 for separation of enantiomers.

Intermediate ak: {cyclopropyl[4-(difluoromethoxy)phenyl]methyl}amine

The title compound was prepared following the procedure described forIntermediate aj (steps 1-3), using 4-difluoromethoxy benzaldehyde (40 g,0.234 mol) and cPrMgBr (0.5 M in THF) in step 1. The title compound wasachieved as a yellow liquid (17 g, 60%). TLC-chloroform/methanol: (9/1):R_(f)=0.1; LCMS (Method 1): 197 [M−16]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ7.44-7.41 (2H, d, J−11.32 Hz), 7.11-7.08 (2H, d, J−11.28 Hz), 7.36-6.99(1H, t), 3.17-3.15 (1H, d), 2.2-1.93 (2H, bs), 0.94-0.89 (1H, m),0.46-0.41 (1H, m), 0.35-0.27 (2H, m), 0.26-0.22 (1H, m).

Intermediate al:cyclopropyl-C-[3-(propane-2-sulfonyl)-phenyl]}-methylamine andIntermediate az: cyclopropyl-[3-(propane-2-sulfonyl)-phenyl]}-methanone

Step 1: 1-bromo-3-(isopropylthio)benzene

2-Bromopropane (5.46 mL, 58.2 mmol) was added dropwise into a mixture of3-bromothiophenol (6.29 mL, 52.9 mmol) and K₂CO₃ (10.96 g, 79.3 mmol) inanhydrous DMF (100 mL), and then stirred at RT overnight. The reactionmixture was diluted with water (200 mL) and extracted with MTBE (3×150mL). The combined organic layers were washed with brine, dried (MgSO₄)and concentrated under reduced pressure to give the title compound as acolourless oil (12.44 g, quantitative), used without furtherpurification. UPLC/MS (max plot) 100%; Rt 2.23 min; (MS+) no signal.

Step 2: cyclopropyl-(3-isopropylsulfanyl-phenyl)-methanone

A 2.5M solution of butyllithium in toluene (21.53 mL, 53.8 mmol) wasadded dropwise over 8 minutes into a solution of1-bromo-3-(isopropylthio)benzene (12.44 g, 53.8 mmol) in anhydroustoluene (125 mL) at RT and the resulting mixture was stirred overnight,and then 1 hour at 40° C. The reaction mixture was cooled at −30° C. andcyclopropanecarbonitrile (4.46 mL, 59.2 mmol) was added dropwise over 10minutes. The resulting orange suspension was stirred at −30° C. for 30minutes and was then allowed to warm up to 0° C. for 1.5 hours. Thereaction mixture was diluted with a 5N aqueous solution of HCl (32.3 mL)over 20 minutes keeping temperature below 10° C., and then stirred at40° C. for 2 hours and at RT for 72 hours. The layers were separated andthe organic one was washed with water, dried (Na₂SO₄) and concentratedunder reduced pressure to give the title compound as a yellow oil (10.38g, 88%), used without further purification. UPLC/MS (max plot) 89.9%; Rt1.97 min; (MS+) 221.3 ([M+H]⁺).

Step 3: C-cyclopropyl-C-[3-(propane-2-sulfonyl)-phenyl]-methylamine(Intermediate al) andcyclopropyl-[3-(propane-2-sulfonyl)-phenyl]}-methanone (Intermediate az)

The title compounds were prepared following procedures described forIntermediate ae (steps 2 to 4), but starting fromcyclopropyl-(3-isopropylsulfanyl-phenyl)-methanone in step 2. Refer toTable 1 for separation of enantiomers.

Intermediate am: Cyclopropyl [3-(ethylsulfonyl) phenyl]methanone

Step 1: Preparation of cyclopropyl [3-(ethylthio) phenyl]methanone

The title compound was prepared following the procedure described forIntermediate al (step 2), but starting from3-Bromo-1-ethanesulfanylbenzene (25.40 g; 116.98 mmol). The crudematerial (23.40 g; crude yield: 96.98%) was obtained as greenish oil,which was used directly without further purification. UPLC/MS: (Method3) MS(ES⁺) 207; ¹H NMR (DMSO, 300 MHz) δ 7.89-7.83 (m, 2H), 7.61-7.56(m, 1H), 7.52-7.46 (m, 1H), 3.10-3.00 (m, 2H), 2.95-2.85 (m, 1H),1.30-1.22 (m, 3H), 1.08-1.00 (m, 4H).

Step 2: Preparation of cyclopropyl [3-(ethylsulfonyl) phenyl]methanone

The title compound was prepared following the procedure described forIntermediate ae (step 2), but starting from cyclopropyl [3-(ethylthio)phenyl] methanone (18.43 g; 80.40 mmol). The crude title product wasobtained as orange oil, which was used directly without furtherpurification [18.28 g; crude yield: 95%; purity: 95%; corrected yield:91%]. UPLC/MS: (Method 3) MS(ES⁺) 239. ¹H NMR (DMSO, 300 MHz) δ8.50-8.45 (m, 2H), 8.24-8.19 (m, 1H), 7.95-7.88 (m, 1H), 3.50-3.42 (m,2H), 3.10-3.00 (m, 1H), 1.22-1.12 (m, 7H).

Intermediate an: C-cyclopropyl-C-(4-ethanesulfonyl-phenyl)]-methylamine

The title compounds were prepared following procedures described forIntermediate ae (steps 1 to 4), but starting from cyclopropanecarbonylchloride in step 1. After purification by flash chromatography (silica,THF), the racemic title compound was obtained as a colourless oil (2.51g, 16% over 4 steps). Refer to Table 1 for separation of enantiomers.

Intermediate ao:C-cyclopropyl-C-[4-(propane-2-sulfonyl)-phenyl]}-methylamine

The title compounds were prepared following procedures described forIntermediate ae (steps 1 to 4), but starting from (isopropylthio)benzeneand cyclopropanecarbonyl chloride in step 1. After purification by flashchromatography (silica, THF), the racemic title compound was obtained asa colourless oil (5.26 g, 30% over 4 steps).

To a solution of tert-Butyl 3-(4-fluorobenzoyl) azetidine-1-carboxylate(14 g, 0.0501 mol) in a mixture of methanol (120 mL) and water (20 mL)was added sodium acetate (10.2 g, 0.1253 mol) followed by hydroxyl aminehydrochloride (6.9 g, 0.1002 mol) at RT. The reaction mixture wasstirred at RT for 12 hr. After completion of the reaction, the reactionmixture was concentrated under reduced pressure. The residue wasdissolved with ethyl acetate (200 mL), washed with an aqueous solutionof sodium bicarbonate (10%, 100 mL), water (100 mL), brine solution (100mL) and dried over sodium sulphate. The solvent was evaporated and thecrude material was purified by column chromatography by using pet etherand ethyl acetate (50:50) as an eluent to afford (13 g, 88%) of thetitle compound as a white solid. TLC: Pet ether/Ethyl acetate: (7/3),R_(f)=0.2; ¹H NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H), 7.41-7.38 (m,2H), 7.25-7.20 (m, 2H), 4.12-4.08 (t, J=8.2 Hz, 1H), 4.04-3.95 (m, 2H),3.82-3.76 (m, 2H), 1.37 (s, 9H).

Refer to Table 1 for separation of enantiomers.

Intermediate ar: C-Cyclopropyl-C-(3-ethanesulfonyl-phenyl)-methylamine

Step 1: C-Cyclopropyl-C-(3-ethylsulfanyl-phenyl)-methylaminehydrochloride

To a 500 mL three necked flask under nitrogen containing3-Bromo-1-ethanesulfanylbenzene 3 (20.00 g; 92.11 mmol; 1.00 eq) in drytoluene (200 mL; 20V) at RT was added rapidly a solution ofn-butyllithium (36.84 mL; 92.11 mmol; 1.00 eq; 2.5M in toluene).Reaction mixture was stirred at RT overnight (Monitoring oflithium-bromine exchange was performed by quenching a sample with CO₂and by injecting resulting carboxylic acid in UPLC/MS: 7% of startingmaterial 3 was left). Reaction mixture was stirred at 40° C. for 4 hr toget lithium-bromine exchange completion.

Temperature was brought down to −30° C. and cyclopropanecarbonitrile(7.64 mL; 101.32 mmol; 1.10 eq) was added drop wise over 10 minutes.Resulting nice orange light suspension was stirred at −30° C. for 2 hrand was then allowed to warm up to 0° C. until completion (Monitoring ofreaction was done by quenching sample with HCl (1N) and followingketimine and ketone formation by UPLC/MS).

Ethanol (100 mL; 5V) was added in one portion and sodium borohydride(6.97 g; 184.22 mmol; 2.00 eq) was added to the resulting colourlesssolution keeping temperature below 10° C. Reaction mixture was stirredat RT over the week-end after what new batch of sodium borohydride (6.97g; 184.22 mmol; 2.00 eq.) was added to get completion after 5 h.Reaction mixture was poured in a large beaker containing HCl (5N, 100mL; careful important foaming). Phases were separated and aqueous phasewas washed with MTBE (2×150 mL) and then basified with NaOH (5N).Aqueous phase was then extracted with MTBE (3×150 mL) and combinedorganic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford colourless oil (m=12.05 g)

This oil was dissolved in 250 mL of diethyl ether at RT and then HCl(2N) in diethyl ether was added drop wise. Resulting white suspensionwas filtered and dried under reduced pressure to give title product[14.21 g; crude yield: 63%; purity: 100%; corrected yield 63%] as whitepowder. UPLC/MS: (Method 3) MS(ES⁺) 207 [M-NH₂]+.

Step 2: Preparation ofC-Cyclopropyl-C-(3-ethanesulfonyl-phenyl)-methylamine

To a solution of C-Cyclopropyl-C-(3-ethylsulfanyl-phenyl)-methylamine(12.00 g; 49.22 mmol; 1.00 eq) in acetic acid (120 mL; 10V) was addedperchloric acid (4.20 mL; 49.22 mmol; 1.00 eq; 70%) in one portion. Thenreaction mixture was cooled down to 15° C. and hydrogen peroxide (50.27mL; 492.21 mmol; 10.00 eq; 30%) was added drop wise over 10 min(exothermic at the beginning of addition) keeping temperature at 20° C.Then solution was stirred at RT for 15 min after what exotherm broughttemperature at 30° C., ice bath was used to maintain temperature at 25°C. for 5 hr until nearly completion.

The reaction was quenched with an excess of NaOH (5N) and the productextracted with dichloromethane. After drying over Na₂SO₄, filtration andconcentration, resulting yellow oil (m=10 g) was purified bychromatoflash (SiO₂, THF) to give the title product [8.00 g; crudeyield: 68%; purity: 91%; corrected yield 62%] as colourless oil (tracesof THF by NMR). UPLC/MS: (Method 3) MS(ES⁺) 239 [M-NH₂]+

Refer to Table 1 for separation of enantiomers.

Intermediate at: tert-butyl3-{amino[4-(trifluoromethoxy)phenyl]methyl}azetidine-1-carboxylate

The title compound was prepared following procedures described forIntermediate ag (steps 1-3), but starting from1-bromo-4-(trifluoromethoxy)benzene (20 g, 0.0786 mol). The titledcompound was achieved as a white solid. TLC-Pet ether/Ethyl acetate(1:1), R_(f)=0.3; ¹H NMR (400 MHz, DMSO-d₆) δ 7.48-7.46 (m, 2H),7.28-7.26 (d, J=8.0 Hz, 2H), 3.91-3.89 (d, J=8.0 Hz, 1H), 3.84-3.79 (bs,2H), 3.59 (bs, 1H), 3.49-3.45 (t, J=8.0 Hz, 1H), 2.67-2.61 (m, 1H), 1.97(bs, 2H), 1.34 (s, 9H). LCMS: (Method 1) 291.01 [M−56]+

Intermediate au:C-[(4-cyclopropanesulfonyl-phenyl)-C-cyclopropyl]-methylamine

The title compounds were prepared following procedures described forIntermediate ae (steps 1 to 4), but starting from(cyclopropylthio)benzene and cyclopropanecarbonyl chloride in step 1.After purification by flash chromatography (silica, THF), the racemictitle compound was obtained as a white solid (2.77 g, 21% over 4 steps).Refer to Table 1 for separation of enantiomers.

Intermediate av: (1R,2R)-2-(4-fluorophenyl)cyclopropanecarbonyl fluoride

Intermediate da (1 gm, 5.55 mmol) was dissolved in DCM (3 mL) and DAST(880 μl, 6.66 mmol) was added to the solution at RT under stirring andnitrogen atmosphere. Reaction was stirred for 1 hr. and then quenched bythe addition of aqueous solution of sodium bicarbonate and extractedwith DCM. Organic layer was separated, dried (MgSO₄) and concentratedunder reduced pressure to get the crude light brown thick oily materialwhich was used without any purification.

Intermediate aw:4-(azido(3-(ethylsulfonyl)phenyl)methyl)tetrahydro-2H-pyran

Step 1: (3-(ethylthio)phenyl)(tetrahydro-2H-pyran-4-yl) methanol

To a solution of 1-Bromo-3-(ethylthio)benzene (720.9 mg, 3.32 mmol) indry THF (5 mL) under N₂ at −78° C. was added 1.9M n-BuLi in cyclohexane(2 mL, 3.80 mmol) drop-wise. The reaction was stirred at thistemperature for 10 mins before addition of 4-formyltetrahydropyran (350μL, 3.36 mmol) drop-wise. The cooling bath was removed and the reactionallowed to achieve ambient temperature over 1 hour. TLC (1:9EtOAc/hexanes) showed the reaction complete. The reaction was quenchedwith sat.NH₄Cl and extracted with Et₂O. The extracts were combined,dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude material was purified by column chromatography eluting with 15-30%EtOAc/hexanes to afford(3-(ethylthio)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (719.1 mg, 2.85mmol, 86%)

Step 2: (3-(ethylsulfonyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol

To a solution of (3-(ethylthio)phenyl)(tetrahydro-2H-pyran-4-yl)methanol(709.1 g, 2.81 mmol) in dry DCM (10 mL) under N₂ at 0° C. was addedmCPBA (5.88 g 26.25 mmol) portion-wise. The reaction was stirred at thistemperature for 1 hour. LCMS showed the reaction complete. The reactionwas quenched with sat.NaHCO₃ and extracted with EtOAc. The extracts werecombined, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by column chromatographyeluting with 30-80% EtOAc/hexanes to afford(3-(ethylsulfonyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (654.9 mg,2.30 mmol, 82%)

Step 3: 4-(azido(3-(ethylsulfonyl)phenyl)methyl)tetrahydro-2H-pyran

To a solution of(3-(ethylsulfonyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (304.2 g,1.07 mmol) in a mixture of dry touene and dry THF (7 mL, 2:5) under N₂at 0° C. was added sequentially DPPA (350 μL, 1.62 mmol) and DBU (250μL, 1.67 mmol) drop-wise. After stirring for 10 min at this temperature,the cooling bath was removed and the reaction allowed to achieve ambienttemperature over 1 hour before heating to 80° C. overnight. LCMS showedthe reaction complete. The reaction was cooled to RT, quenched withsat.NH₄Cl and extracted with EtOAc. The extracts were combined andwashed with H₂O (×2) and brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography eluting with 30-45% EtOAc/hexanes to afford4-(azido(3-(ethylsulfonyl)phenyl)methyl)tetrahydro-2H-pyran (294.7 mg,0.95 mmol, 89%)

Step 4: 4-(azido(3-(ethylsulfonyl)phenyl)methyl)tetrahydro-2H-pyran

To a solution of4-(azido(3-(ethylsulfonyl)phenyl)methyl)tetrahydro-2H-pyran (290.7 mg,0.940 mmol) in MeOH (5 mL) under N₂ was added 10% Pd/C (33.4 mg, ˜11%w/w). The vessel was placed under H₂ atm. and stirred at RT for 2 hours.LCMS showed the reaction complete. The reaction was filtered throughCelite and concentrated under reduced pressure. The crude material waspurified by column chromatography eluting with 3-15% MeOH/DCM to affordthe title compound (210.2 mg, 0.74 mmol, 79%). MS (ES⁺) m/z 284.2(M−H)⁺.

Intermediate ax: Cyclopropyl(2-(2,2-difluoroethoxy)phenyl)benzonitrile

Step 1: Synthesis of 2-(2,2-difluoroethoxy)benzonitrile

To the solution of 2-cyanophenol (5 g, 42.0 mmol) and2,2-difluoroethanol (5.166 g, 63 mmol) in toluene (120 mL) was addedtriphenylphosphine (14.312 g, 54.6 mmol) and reaction mixture wasstirred for 5 min at room temperature. Diisopropyl azodicarboxylate(11.64 mL, 57.6 mmol) was added to the reaction and stirring wascontinued overnight. Reaction was quenched by the addition of saturatedNH₄Cl solution and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered and concentrated under reduced pressure to givethe crude product, which was purified by silica gel columnchromatography using 15% EtOAc in hexane as eluant to afford the titlecompound as colourless oil (7 g, 91%). ¹H NMR (CDCl₃) δ 7.62-7.54 (m,2H), 7.13-6.97 (m, 2H), 6.37-5.98 (m, 1H), 4.36-4.26 (m, 2H).

Step 2: Synthesis ofcyclopropyl(2-(2,2-difluoroethoxy)phenyl)benzonitrile

2-(2,2-difluoroethoxy)benzonitrile (2 g, 10.9 mmo) was dissolved in THF(15 mL) and added dropwise to the cyclopropylmagnesium bromide solution(30.6 mL, 15.3 mmol) at RT under nitrogen atmosphere. After completeaddition, reaction was heated to 50° C. and stirred for 4 hr. Reactionwas cooled to RT and MeOH (25 mL) was added followed by the sequentialaddition of sodium borohydride (826 mg). Reaction was quenched by theslow addition of saturated NH₄Cl solution and extracted with ethylacetate. The organic layer was separated, dried (MgSO₄), filtered andconcentrated under reduced pressure to give the crude material, whichwas purified by column chromatography to afford title compound as whitesolid (1.3 g, 52%). ¹H NMR (CDCl₃) δ 7.48-6.81 (m, 4H), 6.31-5.92 (m,1H), 4.26-4.16 (m, 2H), 3.47 (d, J=8.7 Hz, 1H), 1.66-1.17 (m, 1H),0.66-0.57 (m, 1H), 0.49-0.20 (m, 3H). MS (ES⁺) (Method 2) m/z 226.2(M−H)⁺.

Intermediate ay: Cyclopropyl(2-(trifluoromethoxy)phenyl)benzonitrile

2-(2,2-difluoroethoxy)benzonitrile (as per Intermediate ax, step 1) (2g, 10.7 mmo) was dissolved in THF (15 mL) and added dropwise to thecyclopropylmagnesium bromide solution (32.1 mL, 16.0 mmol) at RT undernitrogen atmosphere. After complete addition, reaction was heated to 50°C. and stirred for overnight. Reaction was cooled to RT and MeOH (25 mL)was added followed by the sequential addition of sodium borohydride (809mg). Reaction was quenched by the slow addition of saturated NH₄Clsolution and extracted with ethyl acetate. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated under reducedpressure to give pale yellow gummy material, which was used without anypurification. MS (ES⁺) (Method 2) m/z 230.2 (M−H)⁺.

Intermediate fa: 1-[4-(propane-2-sulfonyl)-phenyl]-propan-1-one

The title compound was prepared following procedures described forIntermediate ae (steps 1 and 2), but starting from(isopropylthio)benzene in step 1. After purification by flashchromatography (silica, cHex/EtOAc 6:4), followed by trituration inEt₂O, the title compound was obtained as a white powder (2.1 g, 26% over2 steps). ¹H NMR (300 MHz, DMSO-d₆) δ 8.33-8.11 (m, 2H), 8.07-7.89 (m,2H), 3.59-3.43 (m, 1H), 3.14 (q, J=7.1 Hz, 2H), 1.24-1.02 (m, 9H). HPLC(max plot) 99.3%; Rt 3.21 min. UPLC/MS (max plot) 100%; Rt 1.24 min;(MS+) 258.3 ([M+NH₄]⁺).

Intermediate fb: 4-(3-trifluoromethyl-benzoyl)-piperidine-1-carboxylicacid tert-butyl ester

A solution of 1-bromo-3-trifluoromethyl-benzene (1.70 g, 7.56 mmol) inanhydrous Et₂O (7 mL) was added dropwise over 5 minutes into a 1.6Msolution of butyllithium in hexanes (4.72 mL, 7.56 mmol) in anhydrousEt₂O (35 mL) cooled at −78° C. After 15 minutes at −78° C., a solutionof tert-butyl 4-[methoxy(methyl)amino]carbonyl-piperidine-1-carboxylate(2.06 g, 7.56 mmol) in anhydrous Et₂O (7 mL) was added dropwise over 5min. After 1 hour at −78° C., the cooling bath was removed and water (25mL) was added and the mixture was allowed to come back at RT. Theresulting mixture was diluted with Et₂O (30 mL) and the layers wereseparated. The organic layer was washed with water (2×25 mL) and brine(25 mL), dried (Na₂SO₄) and concentrated under reduced pressure to give2.44 g of a pale yellow oil. This oil was dissolved in MeOH (12 mL),then water (6 mL) was added slowly. The precipitate was filtered off,washed twice with a mixture of MeOH/water (2:1) and dried under reducedpressure to give the title compound as a white powder (1.31 g, 49%). ¹HNMR (300 MHz, DMSO-d₆) δ 8.31 (d, J=7.9 Hz, 1H), 8.23 (s, 1H), 8.03 (d,J=7.8 Hz, 1H), 7.80 (dd, J=7.9, 7.8 Hz, 1H), 3.97 (d, J=12.8 Hz, 2H),3.73 (tt, J=11.3, 3.5 Hz, 1H), 2.92 (br s, 2H), 1.77 (dd, J=12.7, 1.6Hz, 2H), 1.49-1.31 (m, 11H). UPLC/MS (Method 3) (MS-) 356.5 ([M−H]⁻).

Intermediate fc:N-{cyclopropyl[4-(difluoromethoxy)phenyl]methyl}-2-(3,3-difluoropiperidin-1-yl)ethanamine

The title compound was prepared following procedures described forintermediate ab (steps 1-3) using Intermediate ak (1.2 g, 5.63 mmol),(48 over 3 steps). LCMS (Method 2) (ES⁺) 361.2 [M+H]⁺

Intermediate fd:(1R)-1-(4-methoxyphenyl)-N-(pyridin-2-ylmethyl)ethanamine

(R)-(+)-1-(4-Methoxyphenyl)ethylamine (153.6 mg, 1.02 mmol),2-pyridinecarbaldehyde (100 μL, 1.05 mmol) and sodiumtriacetoxyborohydride (345.2 mg, 1.63 mmol) were reacted as describedunder General Procedure A to give the title compound (215.6 mg, 87.2%)as pale yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.56-8.47 (m, 1H),7.63-7.57 (m, 1H), 7.37-7.08 (m, 4H), 6.90-6.85 (m, 2H), 3.84-3.72 (m,6H), 1.39 (d, J=6.6 Hz, 3H). LCMS (Method 2) (ES⁺) m/z 243.3 (M+H⁺)

Intermediate fe:(1S)-1-(4-methoxyphenyl)-N-(pyridin-2-ylmethyl)ethanamine

(S)-(−)-1-(4-Methoxyphenyl)ethylamine (150.9 mg, 1.00 mmol),2-pyridinecarbaldehyde (100 μL, 1.05 mmol) and sodiumtriacetoxyborohydride (341.7 mg, 1.61 mmol) were reacted as describedunder General Procedure A to give the title compound (217.7 mg, 89.8%)as pale yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.56-8.47 (m, 1H),7.63-7.57 (m, 1H), 7.37-7.08 (m, 4H), 6.90-6.85 (m, 2H), 3.84-3.67 (m,6H), 1.39 (d, J=6.6 Hz, 3H). LCMS (Method 2) (ES⁺) m/z 243.3 (M+⁺)

Intermediate fg:1-(2,3-dihydro-1H-inden-5-yl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}ethanamine

1-Indan-5-yl-ethylamine (170 mg, 1.054 mmol),6-(trifluoromethyl)pyridine-3-carboxaldehyde (203 mg, 1.159 mmol),sodium triacetoxyborohydride (447 mg, 2.108 mmol) and acetic acid (190mg, 3.163 mmol) were reacted using General Procedure A. The crudematerial was purified by flash chromatography (silica-gel, EtOAc/DCM3:7) to give the title compound (60 mg, 18%) as pale yellow oil. ¹H NMR(300 MHz, CDCl₃) δ 8.62 (s, 1H), 7.83 (dd, J=1.5, 8.1 Hz, 1H), 7.61 (d,J=8.1 Hz, 1H), 7.20-7.16 (m, 2H), 7.07 (dd, J=1.5, 8.1 Hz, 1H),3.79-3.68 (m, 3H), 2.90 (t, J=7.5 Hz, 4H), 2.13-2.03 (m, 2H), 1.37 (d,J=6.6 Hz, 3H). LCMS (Method 2) (ES⁺) m/z 321.2 (M+H⁺).

Intermediate fh:4-[amino-(3-ethanesulfonyl-phenyl)-methyl]-piperidine-1-carboxylic acidtert-butyl ester

Step 1: 4-(3-ethylsulfanyl-bezoyl)-piperidine-1-carboxylic acidtert-butyl ester

The title compound was prepared following procedures described forintermediate ai (Step 1), to afford the titled compound as colourlessliquid. TLC-Pet ether/Ethyl acetate (8:2), R_(f)=0.7; ¹H NMR (400 MHz,DMSO-d₆) δ 7.80 (s, 2H), 7.79-7.69 (dd, J=7.7, 1.0 Hz, 1H), 7.58-7.55(m, 1H), 7.49-7.45 (t, J=14 Hz, 1H) 3.96-3.93 (d, J=12 Hz, 2H) 3.62 (s,1H) 3.06-3.01 (m, 2H) 2.93-2.91 (t, 2H) 1.75-1.72 (d, J=11.6 Hz, 2H)1.41-1.35 (m, 11H) 1.25-1.23 (m, 3H).

Step 2: 4-(3-ethanesulfonyl-bezoyl)-piperidine-1-carboxylic acidtert-butyl ester

The title compound was prepared following procedures described forGeneral Procedure Q using4-(3-ethylsulfanyl-bezoyl)-piperidine-1-carboxylic acid tert-butyl ester(11 g, 0.025 mol). The titled compound (8 g, 66%) was achieved as an offwhite solid. TLC-Pet ether/Ethyl acetate (5:5), R_(f)=0.5; ¹H NMR (400MHz, DMSO-d₆) δ 8.36-8.34 (dd, J=8.0, 1.1 Hz, 2H), 8.15-8.12 (m, 1H),7.83-7.81 (t, J=8.0 Hz, 1H), 4.02-3.98 (dd, J=14.8, 6.8 Hz, 2H)3.74-3.71 (m, 1H) 3.52-3.67 (m, 2H) 2.91 (bs, 2H) 1.79-1.76 (d, J=12 Hz,2H) 1.42-1.39 (m, 11H) 1.12-1.08 (t, J=16 Hz, 3H).

Step 3:4-[amino-(3-ethanesulfonyl-phenyl)-methyl]-piperidine-1-carboxylic acidtert-butyl ester

The title compound was prepared following procedures described forintermediate ai (Steps 5 and 6), using4-(3-ethylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butylester (8 g, 0.020 mol). The titled compound was achieved as a colourlessliquid (2.5 g, 52%). TLC-Pet ether/Ethyl acetate (4:6), R_(f)=0.2; ¹HNMR (400 MHz, DMSO-d₆) δ 7.80 (s, 1H), 7.71-7.00 (d, J=4.0 Hz, 1H),7.66-7.64 (d, J=8.0 Hz, 1H), 7.59-7.57 (t, J=16.0 Hz, 1H), 3.95-3.85 (m,2H), 3.71-3.22 (m, 1H), 3.28-3.22 (m, 2H) 2.53-2.48 (m, 2H), 2.03-1.99(m, 2H), 1.74-1.71 (m, 1H), 1.59-1.53 (m, 1H), 1.35 (bs, 9H), 1.22-1.19(m, 1H), 1.09-0.99 (m, 3H), 0.97-0.96 (m, 1H). LCMS: (Method 1) 282.5[M+100].

Intermediate fi:1-(2,4-difluorophenyl)-1-(1-methylpiperidin-4-yl)methanamine

Step 1:1-(2,4-difluorophenyl)-N-hydroxy-1-(1-methylpiperidin-4-yl)methanimine

1-(2,4-difluorophenyl)-N-hydroxy-1-(piperidin-4-yl)methaniminehydrochloride was reacted according to General Procedure Q to give thetitle compound.

Step 2: 1-(2,4-difluorophenyl)-1-(1-methylpiperidin-4-yl)methanamine

1-(2,4-difluorophenyl)-N-hydroxy-1-(1-methylpiperidin-4-yl)methanimine(1 eq.) was dissolved in the smallest amount of THF (1 mL per 150 mgoxime) and the mixture cooled to 0° C. before addition of 70% aqueousformic acid (5 mL per 150 mg oxime). Once added the mixture was allowedto attain ambient temperature and zinc powder (30 eq.) was added portionwise over 15 min. The reaction mixture was stirred until complete (1.5hr) at room temperature. Once complete the mixture was filtered throughCelite and washed with EtOAc. The filtrate was neutralized with aconcentrated ammonia solution to pH 8 and then extracted with 10% MeOHin DCM (×3). The combined organics were then dried (MgSO₄), concentratedunder reduced pressure to yield 1.368 g, 88% of1-(2,4-difluorophenyl)-1-(1-methylpiperidin-4-yl)methanamine. LCMS(Method 2) 241.3 [M+H]⁺

Intermediate fi: 1-[4-(difluoromethoxy)phenyl]-2-methoxyethanamine

Step 1: 1-(difluoromethoxy)-4-ethenylbenzene

To a solution of methyl triphenylphosphonium iodide (2.348 g) inanhydrous diethyl ether (40 mL) under a nitrogen atmosphere was addedKOBu^(t) (0.913 g) portion-wise. The mixture was stirred for 5 minutes,after which time 4-difluoromethoxybenzaldehyde (1 g) was added drop-wiseas a solution in anhydrous diethyl ether (10 mL), once added the mixturewas stirred until complete. Once complete most of the diethyl ether wasremoved under reduced pressure, being very careful not to remove thealkene, pentane (100 mL) was then added. The mixture was filteredthrough a plug of silica gel eluting with 5% diethyl ether in pentane.The collection of alkene was monitored by TLC and once no further alkenewas coming through the filtration was stopped and the diethyl ether andpentane mixture removed under reduced pressure, again being careful notto remove the volatile alkene. This gave ˜500 mg of1-(difluoromethoxy)-4-ethenylbenzene, ˜50% yield which contained smallamounts of diethyl ether and pentane and was used as such in Step 2.

Step 2: benzyl I{1-[4-(difluoromethoxy)phenyl]-2-hydroxyethyl} carbamate

Synthesis of benzyl I{1-[4-(difluoromethoxy)phenyl]-2-hydroxyethyl}carbamate was performed as outlined in J. Am. Chem. Soc., 1998, p 1207using 1-(difluoromethoxy)-4-ethenylbenzene to give 401 mg, 40% yield.

Step 3: benzyl {1-[4-(difluoromethoxy)phenyl]-2-methoxyethyl} carbamate

To a solution of benzyl {1-[4-(difluoromethoxy)phenyl]-2-hydroxyethyl}carbamate (1 eq.) in anhydrous acetone (1 mL per 50 mg alcohol) wasadded MeI (5 eq.) followed by Ag₂O (5 eq.) under nitrogen. The vesselwas sealed to prevent MeI evaporation and stirred for 1 day. After thistime additional MeI (2 eq.) was added and the vessel sealed again andstirred for 2 days. After this time the mixture was filtered throughCelite washing with EtOAc, the filtrate was concentrated under reducedpressure and the crude material purified by column chromatographyeluting with 30% EtOAc in hexanes, giving the title compound inquantitative yield (265 mg).

Step 4: 1-[4-(difluoromethoxy)phenyl]-2-methoxyethanamine

To a solution of benzyl {1-[4-(difluoromethoxy)phenyl]-2-methoxyethyl}carbamate (1 eq.) in methanol (4 mL per 150 mg Cbz protected amine)under a nitrogen atmosphere was added Pd/C (10% by weight). Theatmosphere was then changed to hydrogen and the mixture left to stiruntil complete (0.5 hr). Once complete the mixture was filtered throughCelite to give 177 mg, 94% of the crude material1-[4-(difluoromethoxy)phenyl]-2-methoxyethanamine. LCMS (Method 2) 218.2(M+H)⁺

Intermediate fk:1-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}ethanamine

To a suspension of 1-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]ethanaminedihydrochloride hydrochloride (300 mg, 1.32 mmol) and6-(trifluoromethyl)nicotinaldehyde (210 mg, 1.20 mmol) in anhydrous THFwas added K₂CO₃ (0.183 mg, 1.32 mmol) and stirred for 1 hour. Thereaction was quenched by addition of MeOH, filtered and NaBH₄ (181 mg,4.78 mmol) was added and the reaction mixture stirred until complete byLCMS. The reaction was partitioned between EtOAc and NaHCO₃ (sat. aq.).The organic phase was loaded straight onto a column and eluted with 100%EtOAc to give 80 mg (21%) of the title compound. MS (ES⁺) m/z 314.3(M+H⁺)

TABLE 1 Separation of Chiral Intermediates Seperation Conditions RacemicBuilding (column, eluent, First Eluting arbitrary Second Elutingarbitrary Block Source flow rate) stereochemical assignmentstereochemical assignment

Intermediate ae HPLC Chiralpak AY-H, EtOH/0.1% Et₂NH

  Intermediate bc

  Intermediate bd

Intermediate af HPLC Chiralpak AY-H, EtOH/0.1% Et₂NH

  Intermediate be

  Intermediate bf

alpha-Methyl-4- (methylsulphonyl) benzylamine from ABCR GmbH & Co. KGHPLC Chiralpak AY-H, 250 × 20 mm, 50% Heptane- 50% EtOH + 0.1% DEA; 10ml/min

  Intermediate bg

  Intermediate bh

Intermediate ah SFC Prep 80, Column, Phenomenex Lux-C4 (250 × 30) mm, 5micron, Mobile phase: CO₂: 0.5% DEA in IPA (60:40), Total Flow- 40g/min. Cycle time: 15 min., injection volume: 250 μl (75 mg/injection),Tolal Run time: 20 min and

  Intermediate bi (Rt 4.35 min.)

  Intermediate bj (Rt 6.93 min.)

1-(4-fluoro-phenyl)-2- methyl-propylamine purchased from Enamine Ltdchiral prep. HPLC (condition: Chiralpak IC, 250 × 20 mm, ACN + 0.1% DEAat 10 ml/min)

  Intermediate bk (Rt 7.93 min.)

  Intermediate bl (Rt 8.72 min.)

Intermediate aj CHIRAL HPLC Method: 0.2% DEA in HEXANE: IPA: 80:20,Flow-1.0 ml/min Column: CHIRALCEL OD-H (250 × 4.6) mm, 5μm

  Intermediate bm (Rt 4.8 min.)

  Intermediate bn (Rt 6.5 min.)

(4-fluorophenyl) (cyclopropyl) methanamine from Enamine Ltd. HPLCChiralpak IC, 250 × 20 mm, ACN + 0.1% DEA at 10 ml/min

  Intermediate bo (Rt 8.40 min.)

  Intermediate bp (Rt 8.90 min.)

(4-chlorophenyl) (cyclopropyl) methanamine hydrochloride from EnamineLtd. HPLC Chiralpak AY-H 250 × 20 mm, EtOH + 0.1% DEA, 10 ml/min

  Intermediate bq (Rt 7.18 min.)

  Intermediate br (Rt 8.75 min.)

Intermediate ak HPLC CHIRALCEL OD-H (250 × 21) mm, 0.2% DEA in HEXANE:IPA: 90:10, Flow- 12.0 ml/min, 20 min/injection

  Intermediate bt

  Intermediate bs (Rt 9.154 min.)

Intermediate al HPLC Chiralpak AY-H, heptane/EtOH/Et₂NH 50:50:0.1

  Intermediate bu

  Intermediate bv

Intermediate an HPLC Chiralpak AY-H, EtOH/0.1% Et₂NH

  Intermediate bw

  Intermediate bx

Intermediate ao chiral HPLC (Chiralpak AY-H, EtOH/0.1% Et₂NH):

  Intermediate by

  Intermediate bz

Intermediate ar Chiralpak AY-H, 250 × 20 mm 5 um using Heptane/EtOH/DEA(60/40/0.1) as eluent (feed concentration: 114 mg/ml; flow 10 ml/min).

  Intermediate cb

  Intermediate ca

Intermediate au HPLC Chiralpak AY-H, EtOH/0.1% Et₂NH

  Intermediate cd

  Intermediate ce

1-(1-methyl-1H-1,2,4 triazol-5-yl)-1- propanamine from ABCR GmbH & Co.KG HPLC Chiralpak IC, 250 × 20 mm, 5μm, Heptane/EtOH + 0.1% DEA: 60/4010 ml/min

  Intermediate gc (Rt 10.28 min.)

  Intermediate gd (Rt 12.45 min.)

2-Methoxy-1-(1- methyl-1H-pyrazol-5- yl)ethanamine, from ABCR GmbH & Co,KG HPLC Chiralpak IC, 250 × 20 mm, ACN + 0.1% DEA at 10 ml/min

  Intermediate ge (Rt 10.35 min.)

  Intermediate gf (Rt 12 min.)

(4-flurorphenyl) (oxolan- 2-yl)methanamine, purchased from Enamine LtdHPLC CHIRAL CEL OD-H (250 × 21) mm, 0.1% DEA in HEXANE: IPA: 90:10

  Intermediate gh

  Intermediate gi

  trans-racemate trans-2-(4- fluorophenyl) cyclopropane- carboxylic acidHPLC Chiralpak ADH (250 × 20) mm (Daicel), hetane/ EtOH/formic acid90/10/01/ v/v/v, 0.7 mL/min),

  Intermediate gj

  Intermediate da

3-(4-Fluorophenyl) butanoic acid HPLC Chiralcel OJH 250 × 20 mm column(Daicel) (eluent heptane/ EtOH/iPrOH (90/5/5) v/v/v, 0.1% (v/v) Formicacid, flow 10 mL/min

  Intermediate gh

  Intermediate di

TABLE 2 Acid to Acid Chloride Intermediates Int: Gen. Int. Structure #Proc. Structure #

da J

ea

db J

eb

dc J

ec

de J

ed

df J

ef Where indicated the chiral acids or acid chlorides are racemicmixtures of enantiomers, otherwise chiral acids or chiral acid chloridesare enantiopure and the absolute stereochemistry is not known

Example 1:N-[cyclopropyl(4-methoxyphenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

Intermediate a (25 mg, 0.09 mmol) was reacted with Intermediate nn (46.7mg, 0.23 mmol) in presence of triethylamine (26 μl, 0.19 mmol) accordingto General Procedure C to afford the title compound (34 mg, 84%) asclear oil. ¹H NMR (CDCl₃) δ 8.52-8.37 (m, 1H), 7.65-7.43 (m, 1H),7.30-6.70 (m, 10H), 5.19-4.96 (m, 1H), 4.55-4.12 (m, 2H), 3.81-3.77 (m,3H), 3.57-3.47 (m, 1H), 2.79-2.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-0.15(m, 4H). ¹H NMR (d₆-DMSO, 110° C.) δ 8.42 (br s, 1H), 7.61-7.56 (m, 1H),7.27-6.99 (m, 8H), 6.84-6.81 (m, 2H), 4.72-4.67 (m, 2H), 4.34 (t, J=17.7Hz, 1H), 3.75 (s, 3H), 3.42-3.32 (m, 1H), 2.80-2.43 (m, 2H), 1.28-1.12(m, 4H), 0.68-0.61 (m, 1H), 0.32-0.12 (m, 3H). LCMS (Method 2) Rt 2.346min (98.2% purity), m/z 433.3 (M+H)⁺.

Example 2:N-[cyclopropyl(4-methoxyphenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

Intermediate a (30 mg, 0.11 mmol) was reacted with3-(4-fluorophenyl)propanoyl chloride (41.7 mg, 0.22 mmol) in presence oftriethylamine (31.2 μl, 0.22 mmol) according to General Procedure C toafford the title compound (32 mg, 68%) as clear oil. ¹H NMR (CDCl₃) δ8.49-8.41 (m, 1H), 7.56-7.50 (m, 1H), 7.26-7.05 (m, 6H), 6.99-6.89 (m,2H), 6.84-6.78 (m, 2H), 5.20-5.11 (m, 1H), 4.51-4.09 (m, 2H), 3.79 (brs, 3H), 3.06-2.90 (m, 2H), 2.75-2.47 (m, 2H), 1.04-0.95 (m, 1H),0.79-0.66 (m, 1H), 0.39-0.28 (m, 2H), 0.12-0.04 (m, 1H). LCMS (Method 2)Rt 2.192 min (96.6% purity), m/z 419.2 (M+H)⁺.

Example 3:(3R)—N-[cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

Intermediate b (30 mg, 0.11 mmol) was reacted with Intermediate ei (44mg, 0.22 mmol) in presence of triethylamine (31 μl, 0.22 mmol) accordingto General Procedure C to afford the title compound (42 mg, 88%) asclear oil. ¹H NMR (CDCl₃) δ 8.53-8.36 (m, 1H), 7.65-7.44 (m, 1H),7.33-6.82 (m, 10H) 5.21-4.96 (m, 1H), 4.57-4.06 (m, 2H), 3.58-3.42 (m,1H), 2.74-2.28 (m, 2H), 1.33-1.24 (m, 4H), 0.98-0.82 (m, 1H), 0.76-0.56(m, 1H), 0.40-0.18 (m, 2H). HPLC (Method 2) Rt 2.831 min (100% purity).MS (ES⁺) m/z 437.3 (M+H⁺).

Example 4:(3S)—N-[cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

Intermediate b (30 mg, 0.11 mmol) was reacted with Intermediate oo (44mg, 0.22 mmol) in presence of triethylamine (31 μl, 0.22 mmol) accordingto General Procedure C to afford the title compound (43 mg, 90%) asclear oil. ¹H NMR (CDCl₃) δ 8.52-8.36 (m, 1H), 7.65-7.43 (m, 1H),7.33-6.82 (m, 10H) 5.21-4.96 (m, 1H), 4.57-4.05 (m, 2H), 3.58-3.42 (m,1H), 2.74-2.28 (m, 2H), 1.33-1.24 (m, 4H), 0.98-0.82 (m, 1H), 0.78-0.55(m, 1H), 0.40-0.18 (m, 2H). HPLC (Method 2) Rt 2.809 min (100% purity).MS (ES⁺) m/z 437.3 (M+H⁺).

Example 5: Diastereomer A of(3R)—N-[1-cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide,and Example 6: Diastereomer B of(3R)—N-[1-cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

Example 3 was a diastereomeric mixture and was resolved by on Prep LC4000 with 2777C Sample Manager PAL (loop: 5 ml) and Waters Fractioncollector Ill, equipped with Waters 2487 Dual Detector using ChiralpakADH 250×20 mm (Daicel) (eluent hexane EtOH DEA 85/15/01 v/v/v, flow 10ml min) to afford compound 5 (first eluting) and compound 6 (secondeluting).

Example 7: Diastereomer A of(3S)—N-[1-cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide,and Example 8: diastereomer B of(3S)—N-[1-cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

Example 4 was a diastereomeric mixture and was resolved by on Prep LC4000 with 2777C Sample Manager PAL (loop: 5 ml) and Waters Fractioncollector Ill, equipped with Waters 2487 Dual Detector using ChiralpakIA 250×20 mm (eluent hexane ISOH 50/50 v/v, flow 10 ml min) to affordcompound 7 (first eluting) and compound 8 (second eluting).

Example 9:N-[cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

Intermediate b (30 mg, 0.11 mmol) was reacted with3-(4-fluorophenyl)propanoyl chloride (41 mg, 0.22 mmol) in presence oftriethylamine (31 μl, 0.22 mmol) according to General Procedure C toafford the title compound (40 mg, 86%) as clear oil. ¹H NMR (CDCl₃) δ8.49-8.38 (m, 1H), 7.58-7.50 (m, 1H), 7.28-6.90 (m, 10H) 5.19-5.11 (m,1H), 4.53-4.07 (m, 2H), 3.05-2.95 (m, 2H), 2.70-2.51 (m, 2H), 1.18-0.92(m, 1H), 0.86-0.68 (m, 1H), 0.58-0.49 (m, 1H), 0.40-0.27 (m, 2H). LCMS(Method 2) Rt 2.605 min (100% purity), m/z 423.3 (M+H)⁺.

Example 10:N-[(4-chlorophenyl)(cyclopropyl)methyl]-2-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)cyclopropanecarboxamide

Intermediate b (23 mg, 0.08 mmol) was reacted with Intermediate qq (33.5mg, 0.17 mmol) in presence of triethylamine (23.5 μl, 0.17 mmol)according to General Procedure C to afford the title compound (28 mg,76%) as clear oil. ¹H NMR (CDCl₃) δ 8.44-8.35 (m, 1H), 7.65-6.80 (m,11H), 5.22-5.07 (m, 1H), 4.78-4.28 (m, 2H), 2.52-2.43 (m, 1H), 1.88-1.66(m, 2H), 1.30-1.05 (m, 2H), 0.90-054 (m, 2H), 0.48-0.12 (m, 2H). LCMS(Method 2) Rt 2.652 min (98.4% purity), m/z 435.2 (M+H)⁺.

Example 13: Diastereomer C ofN-[(4-chlorophenyl)(cyclopropyl)methyl]-2-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)cyclopropanecarboxamide

Intermediate d (75 mg, 0.28 mmol), Intermediate gj (63 mg, 0.35 mmol),triethylamine (74 μl, 0.42 mmol) and T3P (330 μl, 0.55 mmol) werereacted according to General Procedure D to afford the titled compound(77 mg, 64%) as a pale yellow oil. ¹H NMR (CDCl₃) δ 8.48-8.35 (m, 1H),7.67-7.42 (m, 1H), 7.39-7.23 (m, 5H), 7.16-6.96 (m, 1H), 6.90-6.79 (m,4H), 5.21-5.15 (m, 1H), 4.78-4.36 (m, 2H), 2.50-2.44 (m, 1H), 1.84-1.78(m, 1H), 1.74-1.66 (m, 1H), 1.25-1.07 (m, 2H), 0.82-0.74 (m, 1H),0.69-0.61 (m, 1H), 0.48-0.23 (m, 2H). HPLC (Method 2) Rt 2.638 min (100%purity). MS (ES⁺) m/z 435.2 (M+H⁺).

Example 14: Diastereomer D ofN-[(4-chlorophenyl)(cyclopropyl)methyl]-2-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)cyclopropanecarboxamide

Intermediate d (73 mg, 0.27 mmol), Intermediate da (60 mg, 0.33 mmol),triethylamine (74 μl, 0.42 mmol) and T3P (330 μL, 0.55 mmol) werereacted according to General Procedure D to afford the titled compound(74 mg, 64%) as a pale yellow oil. ¹H NMR (CDCl₃) δ 8.44-8.42 (m, 1H),7.68-7.53 (m, 1H), 7.39-7.36 (m, 2H), 7.31-7.20 (m, 3H), 7.14-7.05 (m,1H), 6.95-6.83 (m, 4H), 5.20-5.07 (m, 1H), 4.79-4.29 (m, 2H), 2.51-2.45(m, 1H), 1.90-1.83 (m, 1H), 1.80-1.70 (m, 1H), 1.28-1.06 (m, 2H),0.80-0.70 (m, 1H), 0.62-0.53 (m, 1H), 0.44-0.33 (m, 1H), 0.29-0.16 (m,1H). HPLC (Method 2) Rt 2.697 min (100% purity). MS (ES⁺) m/z 435.2(M+H⁺).

Example 21:N-[cyclopentyl(4-fluorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

Intermediate i (125 mg, 0.44 mmol), 3-(4-fluorophenyl)propionic acid(148 mg, 0.88 mmol), triethylamine (0.12 mL, 0.88 mmol) and T3P (0.84mL, 1.32 mmol) were reacted according to General Procedure D to give thetitle compound as a yellow oil. ¹H NMR (d₆-DMSO) δ 8.35-8.31 (m, 1H),7.46-6.92 (m, 10H), 6.57-6.38 (m, 1H), 5.58-4.90 (m, 1H), 4.60-4.46 (m,2H), 3.23-2.68 (m, 4H), 2.48-2.36 (m, 1H), 1.61-1.36 (m, 6H), 1.26-0.87(m, 2H). HPLC (Method 1) Rt 3.80 min (Purity: 99.9%). UPLC/MS (Method 3)435.2 (M+H)⁺.

Example 24:3-(4-fluorophenyl)-N-[1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)propyl]-N-(pyridin-2-ylmethyl)propanamide

Intermediate l (60 mg, 0.21 mmol), 3-(4-fluorophenyl)propionic acid (54mg, 0.32 mmol), T3P (178 μl, 0.32 mmol) and triethylamine (29 μl, 0.21mmol) were reacted according to General Procedure D to give the titlecompound as a colourless oil (51 mg). ¹H NMR (d₆-DMSO) δ 8.42-8.33 (m,1H), 7.56-7.46 (m, 1H), 7.38-6.94 (m, 7H), 6.81-6.76 (m, 1H), 6.58-6.52(m, 1H), 5.65-4.96 (m, 1H), 4.89-4.77 (m, 1H), 4.48-4.22 (m, 2H),3.24-2.81 (m, 4H), 2.70-2.52 (m, 2H), 1.93-1.66 (m, 2H), 1.33-1.31 (m,3H), 0.77-0.70 (m, 3H). HPLC (Method 1) Rt 3.36 min (Purity: 100.0%).UPLC/MS (Method 3) 433.4 (M+H)⁺.

Compound 39: Diastereomer A ofN-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}butanamide& Compound 40: Diastereomer B ofN-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}butanamide

Intermediate fg (50 mg, 0.156 mmol) was reacted with Intermediate nn (79mg, 0.390 mmol) in presence of TEA (44 μl, 0.312 mmol) using GeneralProcedure C to afford racemic compounds 39 and 40 (arbitrarily assignedabove). The crude material was purified over PTLC (silica-gel, DCM)Compound 39 (25 mg, 33%) was eluted first as clear oil. ¹H NMR (300 MHz,DMSO, 110° C.) δ 8.31 (bs, 1H), 7.57-7.45 (m, 2H), 7.36-7.27 (m, 3H),7.09-6.96 (m, 4H), 5.66 (bs, 1H), 4.51-4.36 (m, 2H), 3.43-3.33 (m, 1H),2.86-2.73 (m, 5H), 2.16-1.88 (m, 3H), 1.40 (d, J=7.2 Hz, 3H), 1.27 (d,J=6.9 Hz, 3H). ¹H NMR (300 MHz, CDCl₃) δ 8.38-8.21 (m, 1H), 7.52-6.72(m, 9H), 6.16-5.18 (m, 1H), 4.54-4.14 (m, 2H), 3.57-3.48 (m, 1H),2.96-2.38 (m, 5H), 2.24-1.86 (m, 2H), 1.37-1.27 (m, 7H). HPLC (Method 2)Rt 3.670 min (96% purity). MS (ES⁺) m/z 485.2 (M+H⁺) Compound 40 waseluted second (28 mg, 37%) as clear oil. ¹H NMR (300 MHz, CDCl₃) δ8.28-8.14 (m, 1H), 7.42-6.55 (m, 9H), 6.14-5.15 (m, 1H), 4.41-4.22 (m,2H), 3.60-3.48 (m, 1H), 2.99-2.38 (m, 5H), 2.06-1.95 (m, 2H), 1.53 (d,J=7.2 Hz, 3H), 1.37 (d, J=6.9 Hz, 3H), 1.31-1.25 (m, 1H). HPLC (Method2) Rt 3.562 min (97.9% purity). MS (ES⁺) m/z 485.2 (M+H⁺).

Example 41:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-[2-(3,6-dimethylpyrazin-2-yloxy)ethyl]butanamide

Intermediate v (70 mg, 0.23 mmol) was reacted with Intermediate nn (113mg, 0.56 mmol) in presence of triethylamine (63 μl, 0.45 mmol) accordingto General Procedure C to afford the title compound (75 mg, 70%) asclear oil. ¹H NMR (CDCl₃) δ 7.86-7.80 (m, 1H), 7.25-6.76 (m, 7H),6.05-4.97 (m, 1H), 4.42-3.12 (m, 5H), 2.91-2.58 (m, 5H), 2.36-2.28 (m,6H), 2.12-1.98 (m, 2H), 1.68-1.26 (m, 7H). LCMS (Method 2) Rt 4.153 min(95% purity), m/z 476.5 (M+H)⁺.

Example 44:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-[2-(6-chloropyridin-2-yloxy)ethyl]butanamide

Intermediate x (67 mg, 0.21 mmol), Intermediate nn and (75 mg, 0.38mmol), DIPEA (60 μl, 0.35 mmol) were reacted according to GeneralProcedure C to afford the titled compound (93 mg, 91%) as a yellow oil.¹H NMR (CDCl₃) δ 7.53-7.44 (m, 1H), 7.30-7.04 (m, 4H), 6.99-6.72 (m,4H), 6.55-6.50 (m, 1H), 6.07-4.97 (m, 1H), 4.38-4.19 (m, 1H), 4.12-3.84(m, 1H), 3.80-3.09 (m, 3H), 2.95-2.74 (m, 5H), 2.70-2.59 (m, 1H),2.12-1.98 (m, 2H), 1.67-1.29 (m, 6H). LCMS (Method 2) Rt 5.132 min (98%purity), m/z 481.2 (M+H)⁺.

Example 45:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-[2-(6-chloropyridin-2-yloxy)ethyl]propanamide

Intermediate x (66 mg, 0.21 mmol), 3-(4-fluorophenyl)propanoyl chloride,(58 mg, 0.31 mmol) and DIPEA (50 μl, 0.29 mmol) were reacted accordingto General Procedure C to afford the titled compound (83 mg, 86%) as ayellow oil. ¹H NMR (CDCl₃) δ 7.51-7.44 (m, 1H), 7.27-7.12 (m, 4H),7.03-6.85 (m, 4H), 6.56-6.48 (m, 1H), 6.10-5.02 (m, 1H), 4.43-4.24 (m,1H), 4.09-3.20 (m, 3H), 3.09-2.98 (m, 2H), 2.94-2.72 (m, 6H), 2.11-2.00(m, 2H), 1.62-1.51 (m, 3H). LCMS (Method 2) Rt 4.592 min (98% purity),m/z 467.3 (M+H)⁺.

Example 46:N-[1-(2,3-dihydro-1H-inden-5-yl}ethyl]-3-(4-fluorophenyl)-N-[2-(pyridin-2-yloxy)ethyl]butanamide

Intermediate y (69 mg, 0.24 mmol), Intermediate nn (71 mg, 0.35 mmol)and DIPEA (60 μl, 0.35 mmol) were reacted according to General ProcedureC to afford the titled compound (98 mg, 90%) as a pale yellow oil. ¹HNMR (CDCl₃) δ 8.10-8.04 (m, 1H), 7.58-7.49 (m, 1H), 7.28-7.04 (m, 4H),6.99-6.76 (m, 4H), 6.64-6.59 (m, 1H), 6.04-4.96 (m, 1H), 4.38-4.23 (m,1H), 4.18-4.02 (m, 1H), 3.87-3.14 (m, 3H), 2.98-2.58 (m, 6H), 2.11-1.98(m, 2H), 1.64-1.29 (m, 6H). LCMS (Method 2) Rt 3.979 min (100% purity),m/z 447.3 (M+H)⁺.

Example 47:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-[2-(pyridin-2-yloxy)ethyl]propanamide

Intermediate y (71 mg, 0.25 mmol), 3-(4-fluorophenyl)propanoyl chloride(72 mg, 0.39 mmol) and DIPEA (60 μl, 0.35 mmol) were reacted accordingto General Procedure C to afford the titled compound (99 mg, 91%) as ayellow oil. ¹H NMR (CDCl₃) δ 8.11-7.97 (m, 1H), 7.56-7.50 (m, 1H),7.24-7.13 (m, 4H), 7.04-6.92 (m, 3H), 6.91-6.81 (m, 1H), 6.65-6.57 (m,1H), 6.07-5.03 (m, 1H), 4.45-4.29 (m, 1H), 4.16-3.22 (m, 3H), 3.07-2.97(m, 2H), 2.94-2.71 (m, 6H), 2.10-1.99 (m, 2H), 1.60-1.52 (m, 3H). LCMS(Method 2) Rt 3.568 min (100% purity), m/z 433.3 (M+H)⁺.

Example 493-(4-fluorophenyl)-N-[(1R)-1-(4-methoxyphenyl)ethyl]-N-(pyridin-2-ylmethyl)butanamide

Intermediate fd (45.6 mg, 0.19 mmol) was reacted with Intermediate nn(45 μL, 0.28 mmol) in presence of TEA (60 μL, 0.43 mmol) as describedunder General Procedure C to afford the crude material. The compound waspurified by silica gel column chromatography (EtOAc/DCM 2:8) to give thetitle compound (64.1 mg, 83%) as a clear oil. ¹H NMR (300 MHz, CDCl₃)δ8.50-8.36 (m, 1H), 7.58-7.39 (m, 1H), 7.28-6.64 (m, 10H), 6.15-5.16 (m,1H), 4.93-4.00 (m, 2H), 3.79-3.76 (m, 3H), 3.59-3.43 (m, 1H), 2.98-2.36(m, 2H), 1.50-1.22 (m, 6H). MS (ES⁺) m/z 407.3 (M+H⁺).

Example 51:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-4-phenyl-N-[2-(pyridin-2-yloxy)ethyl]butanamide

Intermediate y (72 mg, 0.25 mmol), 3-phenylpropanoyl chloride (76 mg,0.41 mmol) and DIPEA (65 pd, 0.38 mmol) were reacted according toGeneral Procedure C to afford the titled compound (96 mg, 88%) as ayellow oil. ¹H NMR (CDCl₃) δ 8.11-8.08 (m, 1H), 7.57-7.49 (m, 1H),7.30-6.95 (m, 8H), 6.88-6.80 (m, 1H), 6.67-6.59 (m, 1H), 6.11-4.99 (m,1H), 4.48-4.28 (m, 1H), 4.20-3.98 (m, 1H), 3.81-3.23 (m, 2H), 2.89-2.84(m, 4H), 2.74-2.67 (m, 2H), 2.59-2.45 (m, 2H), 2.13-1.99 (m, 4H),1.63-1.54 (m, 3H). LCMS (Method 2) Rt 4.078 min (100% purity), m/z 429.2(M+H)⁺.

Example 52:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-[2-(6-methylpyridin-2-yloxy)ethyl]butanamide

Intermediate bb (73 mg, 0.25 mmol), Intermediate nn (71 mg, 0.35 mmol)and DIPEA (60 μl, 0.35 mmol) were reacted according to General ProcedureC to afford the titled compound (103 mg, 91%) as a pale yellow oil. ¹HNMR (CDCl₃) δ 7.45-7.38 (m, 1H), 7.25-7.05 (m, 4H), 6.98-6.90 (m, 2H),6.83-6.65 (m, 2H), 6.44-6.37 (m, 1H), 6.07-4.94 (m, 1H), 4.40-3.98 (m,2H), 3.88-3.10 (m, 3H), 2.93-2.56 (m, 6H), 2.40-2.38 (m, 3H), 2.12-1.98(m, 2H), 1.69-1.43 (m, 3H), 1.37-1.26 (m, 3H). LCMS (Method 2) Rt 5.038min (100% purity), m/z 461.2 (M+H)⁺.

Example 53:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-[2-(6-methylpyridin-2-yloxy)ethyl]propanamide

Intermediate bb (71 mg, 0.24 mmol), 3-(4-fluorophenyl)propanoyl chloride(66 mg, 0.35 mmol) and DIPEA (60 μl, 0.35 mmol) were reacted accordingto General Procedure C to afford the titled compound (74 mg, 70%) as apale yellow oil. ¹H NMR (CDCl₃) δ 7.44-7.38 (m, 1H), 7.22-7.13 (m, 4H),7.04-6.90 (m, 3H), 6.69-6.67 (m, 1H), 6.46-6.36 (m, 1H), 6.07-5.00 (m,1H), 4.45-4.25 (m, 1H), 4.16-3.20 (m, 3H), 3.13-2.92 (m, 2H), 2.89-2.71(m, 6H), 2.40-2.30 (m, 3H), 2.11-2.00 (m, 2H), 1.68-1.53 (m, 3H). LCMS(Method 2) Rt 4.44 min (98% purity), m/z 447.3 (M+H)⁺.

Example 54:N-[1-(2,2-dimethyl-1,3-benzoxathiol-5-yl)ethyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

Intermediate cc (83 mg, 0.28 mmol), 3-(4-fluorophenyl)propionic acid (46mg, 0.28 mmol), triethylamine (0.04 mL, 0.28 mmol) and T3P (0.18 mL,0.28 mmol) were reacted according to General Procedure D to give thetitle compound as a colourless oil (75 mg, 61%). ¹H NMR (CDCl₃) δ 8.40(d, J=4.0 Hz, 0.7H), 8.35 (d, J=4.9 Hz, 0.3H), 7.43 (td, J=7.7, 1.8 Hz,1H), 7.17-6.62 (m, 7H), 6.56 (t, J=8.7 Hz, 1H), 6.04 (q, J=7.1 Hz,0.6H), 5.07 (d, J=6.6 Hz, 0.4H), 4.78 (d, J=16.0 Hz, 0.4H), 4.25 (m,1.6H), 3.64 (t, J=5.7 Hz, 0.2H), 2.95 (dt, J=19.7, 7.2 Hz, 1.8H), 2.77(t, J=7.3 Hz, 0.6H), 2.59-2.38 (m, 1.4H), 1.74 (s, 5H), 1.49 (s, 1H),1.37 (d, J=7.0 Hz, 1H), 1.26 (d, J=7.2 Hz, 2H). HPLC (Method 1) Rt 3.61min (Purity: 97.8%). UPLC/MS (Method 3) 451.3 (M+H)⁺.

Example 55: 3-(4-fluorophenyl)-N-[(1S)-1-(2-methoxyphenyl)ethyl]-N-(pyridin-2-ylmethyl)propanamide

Intermediate dd (80 mg, 0.33 mmol), 3-(4-fluorophenyl)propionic acid (56mg, 0.33 mmol), triethylamine (0.05 mL, 0.33 mmol) and T3P (0.21 mL,0.33 mmol) were reacted according to General Procedure D to give thetitle compound as a brown oil (78 mg, 60%).

¹H NMR (CDCl₃) δ 8.39-8.30 (m, 1H), 7.45-7.37 (m, 1H), 7.29-7.20 (m,2H), 7.20-6.74 (m, 7H), 6.67-6.63 (m, 1H), 6.42-5.47 (m, 1H), 4.61-4.38(m, 2H), 3.70 (s, 3H), 3.13-2.49 (m, 4H), 1.48-1.42 (m, 3H). HPLC(Method 1) Rt 3.17 min (Purity: 99.0%). UPLC/MS (Method 3) 393.3 (M+H)⁺.

Example 57:3-(4-fluorophenyl)-N-{1-[2-(methoxymethyl)phenyl]ethyl}-N-(pyridin-2-ylmethyl)propanamide

Intermediate ff (80 mg; 0.31 mmol), 3-(4-fluorophenyl)propionic acid (58mg, 0.34 mmol), T3P (348 μl, 0.62 mmol) and triethylamine (42 μl, 0.31mmol) were reacted according to General Procedure D to give the titlecompound as a yellow oil. ¹H NMR (d₆-DMSO) δ 8.38-8.33 (m, 1H),7.58-7.35 (m, 2H), 7.28-7.01 (m, 8H), 6.94-6.65 (m, 1H), 6.05-5.53 (m,1H), 4.70-4.06 (m, 4H), 3.24-3.20 (m, 3H), 2.94-2.53 (m, 4H), 1.45-1.31(m, 3H). HPLC (Method 1) Rt 3.30 min (Purity: 100.0%). UPLC/MS (Method3) 407.3 (M+H)⁺.

Example 58: Enantiomer A of3-(4-fluorophenyl)-N-{1-[2-(methoxymethyl)phenyl]ethyl}-N-(pyridin-2-ylmethyl)propanamide

Example 57 (50 mg) was separated by chiral HPLC (AD-H, 250×20 mm, 5 um)using EtOH+0.1% DEA (10 mL/min) to give the title compound (1st elutingpic) as a yellow oil (19 mg). HPLC (Method 1) Rt 3.13 min (Purity:99.4%). UPLC/MS (Method 3) 407.2 (M+H)⁺.

Example 61: N-[(1R)-1-(2-methoxyphenyl)ethyl]-N-(pyridin-2-ylmethyl)-3-[3-(trifluoromethyl)phenyl]propanamide

Intermediate ee (80 mg, 0.33 mmol), 3-(3-trifluoromethylphenyl)propionicacid (72 mg, 0.33 mmol), T3P (0.21 mL, 0.33 mmol) and triethylamine(0.05 mL, 0.33 mmol) were reacted according to General Procedure D togive the title compound as a brown oil (64 mg, 44%). ¹H NMR (CDCl₃) δ8.40-8.29 (m, 1H), 7.54-7.36 (m, 5H), 7.28-7.25 (m, 1H), 7.17-7.12 (m,1H), 7.05-7.65 (m, 3H), 6.67-6.64 (m, 1H), 6.21-5.47 (m, 1H), 4.64-4.40(m, 2H), 3.68-3.67 (m, 3H), 3.23-2.56 (m, 4H), 1.49-1.44 (m, 3H). HPLC(Method 1) Rt 3.68 min (Purity: 100.0%). UPLC/MS (Method 3) 443.3(M+H)⁺.

Example 62:N-[1-(2,2-dimethyl-1,3-benzoxathiol-5-yl)ethyl]-N-(pyridin-2-ylmethyl)-3-[3-(trifluoromethyl)phenyl]propanamide

Intermediate cc (83 mg, 0.28 mmol), 3-(3-trifluoromethylphenyl)propionicacid (60 mg, 0.28 mmol), T3P (0.18 mL, 0.28 mmol and triethylamine (0.04mL, 0.28 mmol) were reacted according to General Procedure D to give thetitle compound as a yellow oil. ¹H NMR (CDCl₃) δ 8.47-8.41 (m, 1H),7.61-7.35 (m, 5H), 7.13-6.60 (m, 5H), 6.14-5.11 (m, 1H), 4.89-4.29 (m,2H), 3.16-3.01 (m, 2H), 2.91-2.57 (m, 2H), 1.80 (s, 6H), 1.45-1.32 (m,3H). HPLC (Method 1) Rt 3.99 min (Purity: 96.8%). UPLC/MS (Method 3)501.4 (M+H)⁺.

Example 63:N-[1-(2,2-dimethyl-3-oxido-1,3-benzoxathiol-5-yl)ethyl]-N-(pyridin-2-ylmethyl)-3-[3-(trifluoromethyl)phenyl]propanamide

To a solution of Example 62 (70 mg, 0.14 mmol) in glacial AcOH (5 mL) at0° C. was added H₂O₂ (0.03 mL, 0.28 mmol). After stirring for 2 hr, H₂O₂(0.12 mL, 1.12 mmol) was added and the stirring continued at RTovernight. Water was added and the aqueous phase was extracted with DCM.The combined organics were then extracted with 1 M NaOH, dried (MgSO₄),filtered and concentrated under reduced pressure. The crude mixture waspurified by MD Autoprep to give the title compound as a vitreous solid.¹H NMR (CDCl₃) δ 8.41-8.29 (m, 1H), 7.79-7.30 (m, 7H), 7.22-6.79 (m,3H), 6.23-5.18 (m, 1H), 4.87-4.29 (m, 2H), 3.26-2.61 (m, 4H), 1.81 (brs, 3H), 1.50-1.39 (m, 6H). HPLC (Method 1) Rt 3.42 min (Purity: 85.9%).UPLC/MS (Method 3) 517.3 (M+H)⁺.

Example 64:N-[1-(2,2-dimethyl-3-oxido-1,3-benzoxathiol-5-yl)ethyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

To a solution of Example 54 (70 mg, 0.16 mmol) in glacial AcOH (5 mL) at0° C. was added H₂O₂ (35 μl, 0.31 mmol). After stirring for 2 hr, H₂O₂(0.14 mL, 1.24 mmol) was added and the stirring continued at RTovernight. Water was added and the aqueous phase was extracted with DCM.The combined organics were then extracted with 1 M NaOH, dried (MgSO₄),filtered and concentrated under reduced pressure. The crude was purifiedby MD Autoprep to give the title compound as a vitreous solid. ¹H NMR(CDCl₃) δ 8.50-8.37 (m, 1H), 7.72-6.82 (m, 10H), 6.22-5.19 (m, 1H),4.85-4.21 (m, 2H), 3.10-2.53 (m, 4H), 1.81 (s, 3H), 1.51-1.37 (m, 6H).HPLC (Method 1) Rt 2.81 min (Purity: 96.0%). UPLC/MS (Method 3) 467.3(M+H)⁺.

Example 65:2-[(4-fluorophenyl)sulfonyl]-N-{1-[2-(methoxymethyl)phenyl]ethyl}-N-(pyridin-2-ylmethyl)acetamideand Example 66:1-[(4-fluorophenyl)sulfonyl]-N-{1-[2-(methoxymethyl)phenyl]ethyl}-N-(pyridin-2-ylmethyl)cyclopropanecarboxamide

Intermediate ff (120 mg, 0.47 mmol),1-[(4-fluorophenyl)sulfonyl]cyclopropanecarboxylic acid (preparedaccording to the procedure outlined in the Bulletin of the ChemicalSociety of Japan 1985, 58(2), 765-6) (172 mg, 0.70 mmol) containing 10%of [(4-fluorophenyl)sulfonyl]acetic acid, T3P (392 μl, 0.70 mmol) andtriethylamine (65 μl, 0.47 mmol) were reacted according to GeneralProcedure D to give Example 65 and Example 66 as brown solids. Example65: HPLC (Method 1) Rt 2.78 min (Purity: 93.7%). UPLC/MS (Method 3)457.1 (M+H)⁺. Example 66: ¹H NMR (CDCl₃) δ 8.44-8.43 (m, 1H), 7.69-7.64(m, 2H), 7.48-7.38 (m, 2H), 7.30-7.07 (m, 6H), 6.75-6.72 (m, 1H),5.80-5.70 (m, 1H), 5.12-5.00 (m, 2H), 4.66-4.62 (m, 1H), 4.27-4.23 (m,1H), 3.36 (s, 3H), 1.95 (br s, 1H), 1.77-1.54 (m, 4H), 1.40 (d, J=7.0Hz, 3H). HPLC (Method 1) Rt 3.11 min (Purity: 97.6%). UPLC/MS (Method 3)483.1 (M+H)⁺.

Example 67:N-[1-(2,3-dihydro-1H-inden-5-yl)ethyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

Intermediate gg (100 mg, 0.40 mmol), 3-(4-fluorophenyl)propionic acid(73 mg, 0.44 mmol), T3P (442 μl, 0.79 mmol) and triethylamine (53 μl,0.40 mmol) were reacted according to General Procedure D to give thetitle compound as a yellow oil. ¹H NMR (d₆-DMSO) δ 8.48-8.46 (m, 1H),7.67-7.58 (m, 1H), 7.32-6.94 (m, 9H), 5.94-5.31 (m, 1H), 4.69-4.01 (m,2H), 2.99-2.65 (m, 8H), 2.02-1.91 (m, 2H), 1.39-1.24 (m, 3H). HPLC(Method 1) Rt 3.68 min.

Example 74: Diastereomer A ofN-[cyclopropyl(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-5-yl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

Intermediate yy (75 mg, 0.21 mmol), Intermediate di (76 mg, 0.42 mmol),triethylamine (87 μl, 0.63 mmol) and T3P (266 mg, 0.42 mmol) werereacted according to General Procedure D to give the title compound as awhite solid (41 mg, 37%). ¹H NMR (CDCl₃) δ 8.52-8.33 (m, 1H), 7.69-7.44(m, 2H), 7.23-6.74 (m, 8H), 5.12 (dd, J=10.4, 4.6 Hz, 1H), 4.55-4.12 (m,2H), 3.56-3.46 (m, 1H), 2.71-2.44 (m, 2H), 1.71 (s, 6H), 1.34-0.23 (m,8H). HPLC (Method 1) Rt 2.63 min (Purity: 98.4%). UPLC/MS (Method 3)523.1 (M+H)⁺.

Example 76: Diastereomer A ofN-[(4-chlorophenyl)(cyclopropyl)methyl]-3-[(4-fluorophenyl)sulfonyl]-N-(pyridin-2-ylmethyl)butanamide

Intermediate b (100 mg, 0.37 mmol), Intermediate do (135 mg; 0.55 mmol),T3P (409 μl, 0.73 mmol) and triethylamine (77 μl, 0.55 mmol) werereacted according to General Procedure D to give the racemic mixture asa pale pink solid. HPLC (Method 1) Rt 3.55 min (Purity: 94.7%). UPLC/MS(Method 3) 501.1 (M+H)⁺. The isomers were separated by SFC Chiralpak ICat 35° C., 20 EtOH, 100 mL/min. The title compound was the first elutingisomer, eluting at 2.98 minutes.

Example 78: Diastereomer A of3-(4-fluorophenyl)-N-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-N-(pyridin-2-ylmethyl)butanamide

Intermediate zz (44 mg, 0.2 mmol), 3-(4-fluorophenyl)butanoic acid (55mg; 0.30 mmol), T3P (226 μl, 0.41 mmol) and triethylamine (42 μl, 0.3mmol) were reacted according to General Procedure D to give the titlecompound as a brown solid. ¹H NMR (d₆-DMSO) δ 8.38-8.30 (m, 1H),7.85-7.80 (m, 1H), 7.56-7.49 (m, 1H), 7.22-7.07 (m, 3H), 6.29-6.17 (m,1H), 4.68-4.36 (m, 2H), 3.53 (s, 1.5H), 3.51-3.41 (m, 1H), 3.14 (s,1.5H), 2.99-2.57 (m, 2H), 1.67-1.55 (m, 3H), 1.29-1.26 (m, 3H). HPLC(Method 1) Rt 2.21 min (Purity: 97.7%). UPLC/MS (Method 3) 382.2 (M+H)⁺.The isomers were separated by HPLC Chiralpak IC:EtOH+0.1% DEA, 10mL/min. The title compound was the first eluting isomer, eluting at 9.44min.

Example 80:N-[(4-chlorophenyl)(cyclopropyl)methyl]-2-[(4-fluorophenyl)sulfonyl]-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)acetamide

Intermediate ad (430 mg, 1.41 mmol), (4-fluoro-benzenesulfonyl)-aceticacid (339 mg, 1.55 mmol), T3P (1.678 mL, 2.82 mmol) and triethylamine(0.393 mL, 2.82 mmol) were reacted according to General Procedure D togive the title compound as a white solid (380 mg, 53%). ¹H NMR (CDCl₃) δ7.99-7.92 (m, 2H), 7.49-7.47 (m, 2H), 7.38-7.35 (m, 2H), 7.30-7.23 (m,2H), 4.69-4.56 (m, 1H), 4.26-4.04 (m, 3H), 3.65-3.44 (m, 2H), 3.03-2.92(m, 1H), 2.61 (d, J=3.9 Hz, 3H), 2.26-1.84 (m, 7H), 1.86-1.75 (m, 1H),0.99-0.90 (m, 1H), 0.81-0.71 (m, 1H), 0.63-0.55 (m, 1H), 0.49-0.41 (m,1H). LCMS (Method 2) Rt 2.59 min (Purity: 99.4%), m/z 505.2 (M+H)⁺.

Example 87:3-(4-Fluorophenyl)-N-[1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-N-(pyridin-2-ylmethyl)butanamide

Intermediate aaa (87 mg, 0.37 mmol), 3-(4-fluorophenyl)butanoic acid(102 mg; 0.56 mmol), T3P (418 μl, 0.75 mmol) and triethylamine (78 μl,0.56 mmol) were reacted according to General Procedure D to give thetitle compound as a brown oil. ¹H NMR (de-DMSO) δ 8.59-8.52 (m, 1H),7.78-7.59 (m, 1H), 7.24-7.18 (m, 1H), 7.15-7.09 (m, 2H), 7.03-6.90 (m,3H), 5.94-5.30 (m, 1H), 4.96-4.46 (m, 2H), 3.50-3.40 (m, 1H), 2.94-2.46(m, 4H), 1.76-1.56 (m, 1H), 1.54-1.47 (m, 2H), 1.35-1.31 (m, 1H),1.27-1.20 (m, 5H). HPLC (Method 1) Rt 3.03 min (Purity: 100.0%). UPLC/MS(Method 3) 397.2 (M+H)⁺.

Example 88:N-{cyclopropyl[4-(difluoromethoxy)phenyl]methyl}-3-[(4-fluorophenyl)sulfonyl]-N-[(6-methoxypyridin-3-yl)methyl]butanamide

Intermediate ak (311 mg, 0.93 mmol), Intermediate do (275 mg, 1.12 mmol)T3P (1.48 mL, 2.33 mmol) and triethylamine (0.324 mL, 1.86 mmol) werereacted according to General Procedure D to give the title compound as ayellow oil (64 mg, 12%). LCMS (Method 2) Rt 2.13 min (Purity: 99%) m/z563.3 (M+H)⁺.

Example 89:N—{(R)-cyclopropyl[4-(difluoromethoxy)phenyl]methyl}-2-[1-(4-fluorophenyl)cyclopropyl]-N-(pyridazin-3-ylmethyl)acetamide

Intermediate bt (77 mg, 0.25 mmol), Intermediate eh (84 mg, 0.40 mmol)and triethylamine (0.110 mL, 0.79 mmol) were reacted in Et₂O accordingto General Procedure C to give the title compound as a orange/lightbrown oil (46 mg, 38%). LCMS (Method 2) 482.2 (M+H)⁺.

Example 91: Enantiomer A ofN-{cyclopropyl[4-(difluoromethoxy)phenyl]methyl}-1-[(4-fluorophenyl)sulfonyl]-N-(pyridin-2-ylmethyl)cyclopropanecarboxamideand Example 92: Enantiomer B ofN-{cyclopropyl[4-(difluoromethoxy)phenyl]methyl}-1-[(4-fluorophenyl)sulfonyl]-N-(pyridin-2-ylmethyl)cyclopropanecarboxamide

Intermediate ak (275 mg, 0.094 mmol), Intermediate ds (265 mg, 1.08mmol), T3P (1.44 mL, 2.26 mmol) and triethylamine (0.315 mL, 1.81 mmol)were reacted according to General Procedure D to give the racemicmixture of the title compounds (143 mg, 30%). The isomers were separatedby chiral HPLC according to Method G. The first eluting isomer (12.67min, m/z 532.1 (M+H)⁺) was Enantiomer A and the second eluting isomer(29.53 min, m/z 532.1 (M+H)⁺) was Enantiomer B.

Example 93:N-[(4-chlorophenyl)(cyclopropyl)methyl]-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-(phenylsulfonyl)acetamide

Intermediate ad (250 mg, 0.82 mmol), Intermediate dl (197 mg, 0.984mmol), T3P (0.978 mL, 1.64 mmol) and triethylamine (0.126 mL, 0.902mmol) were reacted according to General Procedure D to give a racemateof the title compound as a glassy solid (250 mg, 63%). LCMS Method 2 m/z487.3 (M+H)⁺.

Example 94: Enantiomer A ofN-[(1-(4-fluorophenyl)-2-methylpropyl]-1-[(4-fluorophenyl)sulfonyl]-N-[2-(4-fluoropiperidin-1-yl)ethyl]cyclopropanecarboxamide

Intermediate ab (104.8 mg, 0.35 mmol), Intermediate es (109 mg, 0.41mmol) and triethylamine (0.082 mL, 0.79 mmol) were reacted in Et₂Oaccording to General Procedure C to give the title compound as a yellowoil (71 mg, 38%). LCMS (Method 2) 523.2 (M+H)⁺.

Example 95: Enantiomer A ofN-[(4-chlorophenyl)(cyclopropyl)methyl]-2-[1-(4-fluorophenyl)cyclopropyl]-N-(pyridin-2-ylmethyl)acetamide

Intermediate c (65 mg, 0.24 mmol), Intermediate dh (47 mg, 0.24 mmol),T3P (0.240 mL, 0.40 mmol) and triethylamine (0.054 mL, 0.30 mmol) werereacted according to General Procedure D to give the title compound as ayellow oil (51 mg, 48%). LCMS (Method 2) 449.2 (M+H)⁺.

Example 96: Enantiomer A of(N-[1-(3-bromophenyl)cyclopropyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

1-(3-bromophenyl)-cyclopropanamine (50 mg, 0.24 mmol)) and Intermediateoo (43 mg, 0.024 mmol), T3P (0.240 mL, 0.040) and triethylamine (0.054mL, 0.30 mmol) were reacted according to General Procedure D to give thetitle compound as a yellow oil (56 mg, 50%. (LCMS (Method 2) 467.0 (M+H)

Example 97: (1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-cyclopropyl-(4-difluoromethoxy-phenyl)-methyl]-pyridazin-3-ylmethyl-amide

Protocols

Steps 1-3: Preparation of Intermediate ak,C—[(R)—C-Cyclopropyl-C-(4-difluoromethoxy-phenyl)]-methylamine

Method as (previously described).

HPLC: 97.6% (AUC), Rt 2.7 min. Method: A—0.1% TFA in H₂O, B—0.1% TFA inACN, Flow 2.0 mL/min; Column: XBridge C8 (50×4.6 mm, 3.5 μm).

LCMS: 98.85% (AUC), Rt 4.5 min, MS(ES⁺) (M−16, 197). Method: A: 10 mMNH₄HCO₃; B—ACN, Flow 1.0 mL/min. Column: XBridge C8 (50×4.6 mm, 3.5 μm).

TLC: chloroform/methanol: (9/1), R_(f)=0.1

¹H NMR (DMSO-d₆, 400 MHz) δ 7.43-7.41 (d, J=9.4 Hz, 2H), 7.35-6.98 (t,2H), 7.10-7.08 (d, J=11.4 Hz, 1H), 3.16-3.14 (d, J=8.0 Hz 1H), 2.0-1.97(bs, 2H), 0.92-0.89 (m, 1H), 0.44-0.41 (m, 1H), 0.33-0.29 (m, 2H),0.26-0.23 (m, 1H).

Step 4: Preparation of I-4 (Intermediate bt)

Chiral separation of 1-D (17.0 g) was performed under the belowconditions:

Chiralcel OD-H, 250×20 mm, 5 μm; Heptane/IPA/DIEA; Concentration 42.5mg/mL; Flow 10 mL/min

to yield the 1st eluting, I-E,C—[(R)—C-Cyclopropyl-C-(4-difluoromethoxy-phenyl)]-methylamine [7.3 g;yield 43%] as a yellow liquid.

HPLC: 92.1% (AUC), Rt 2.1 min. Method: A—0.1% TFA in H₂O, B-0.1% TFA inACN, Flow 2.0 mL/min; Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Chiral HPLC: 100.0% (AUC), Rt 7.7 min. Method: Hexane/IPA/DIEA90/10/0.1, Flow 2.0 mL/min, Column: Chiralcel OD (250×4.6 mm, 5 μm).

UPLC/MS: 87.0% (AUC), Rt 0.8 min, MS(ES⁺) (M−16, 197). Method: A: waterNH₄OAc 10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18(2.1×50 mm, 1.7 μm)

¹H NMR (CDCl₃, 300 MHz) δ 7.29-7.05 (m, 2H), 6.95-6.76 (m, 2H), 6.27 (t,J=73.2 Hz, 1H), 2.98 (d, J=8.6 Hz, 1H), 1.36 (s, 2H), 0.89-0.79 (m, 1H),0.47-0.02 (m, 4H).

Step 5: Preparation of I-5

Under N₂, to a solution ofC—[(S)—C-Cyclopropyl-C-(4-difluoromethoxy-phenyl)]-methylamine (5.5 g;25.79 mmol; 1.00 eq.) and Pyridazine-3-carbaldehyde (2.79 g; 25.79 mmol;1.00 eq.) in DCE (90 mL) was added at RT sodium triacetoxyborohydride(10.93 g; 51.59 mmol; 2.00 eq.) followed by AcOH (4.43 mL; 77.38 mmol;3.00 eq.) (Internal temperature increased to 35° C.). The reactionmixture was stirred at RT for 1.5 hr. until completion. The reaction wasquenched carefully and slowly with a 50% aqueous saturated solution ofK₂CO₃ (100 mL). The product was extracted with DCM (3×150 mL). Combinedorganics were dried over MgSO4, filtered and concentrated under reducedpressure giving the crude product as a brown oil m=9.2 g. It waspurified by flash chromatography (SiO₂) eluting with DCM/MeOH 95:5(Rf=0.33) to yield 6[R)-Cyclopropyl-(4-difluoromethoxy-phenyl)-methyl]-pyridazin-3-ylmethyl-amine[5.8 g; yield 73%] as a yellow oil.

UPLC/MS: 97.5% (AUC), Rt 1.3 min, MS(ES⁺) 306.3). Method: A: waterNH₄OAc 10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18(2.1×50 mm, 1.7 μm).

¹H NMR (CDCl₃, 300 MHz) δ 8.86 (dd, J=4.4, 2.2 Hz, 1H), 7.27-7.10 (m,4H), 6.93-6.81 (m, 2H), 6.30 (t, J=74.1 Hz, 1H), 3.85-3.61 (m, 2H), 2.68(d, J=8.9 Hz, 1H), 2.22 (bs, 1H), 0.93-0.84 (m, 1H), 0.53-0.32 (m, 1H),0.25-0.10 (m, 2H), 0.08-0.01 (m, 1H).

Step 6: Preparation of I-6

A mixture of 4-Fluoro-benzaldehyde (200.0 g, 1.61 mol) and malonic acid(503.1 g, 4.83 mol) and piperidine (25 mL, catalytic amount) in pyridine(1 L) refluxed at 100° C. under nitrogen for 12 h. After cooling to RT,the reaction mixture was quenched by adding to ice cold solution of 6NHCL. The solid was filtered and washed with cold water and dried underreduced pressure to yield I-H (4-Fluorophenyl)acrylic acid [250.0 g;yield 93%] as a white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 12.37 (br s, 1H), 7.77-7.74 (m, 2H),7.60-7.56 (d, J=16.0 Hz, 1H), 7.26-7.21 (m, 2H), 6.51-6.47 (d, J=16.0Hz, 1H).

Step 7: Preparation of I-7

To the mixture of (4-Fluorophenyl)acrylic acid (257.0 g, 1.55 mol) andDMAP (56.74 g, 2.01 mol) in t-Butanol (1 L) was added BOC anhydride(438.7 g, 2.01 mol) in drops. The reaction mixture was heated to 80° C.under nitrogen atmosphere for 12 h. After cooling to RT, solvent wasremoved under reduced pressure. The crude material was stirred with petether (250 mL) and the solid was filtered to yield I-I tert-Butyl(4-fluorophenyl)acrylate [320.0 g; yield 93%] as a white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 7.78-7.74 (m, 2H), 7.56-7.52 (d, J=16.0 Hz,1H), 7.26-7.21 (m, 2H), 6.50-6.46 (d, J=16.0 Hz, 1H), 1.46 (s, 9H).

Step 8: Preparation of I-8

Trimethylsulfoxonium iodide (165.7 g, 0.72 mol) was suspended in dryDMSO (700 mL). To this suspension under ice-cooling, sodium hydride (60%suspension in mineral oil) (32.4 g, 1.35 mol) was carefully added inportions over a time period of 1 h. (Note: exotherm!) Then reactionmixture was stirred at RT for 1 h. To this suspension was added asolution of tert-Butyl (4-fluorophenyl)acrylate (100.0 g, 0.42 mol) indry DMSO (250 mL) and the mixture was stirred at RT for 12 h. Thereaction mixture was carefully quenched by adding to ice-cold solutionof 1.5 M HCl (500 mL) and extracted with EtOAc (3×500 mL). Combinedorganic layer was washed with water (500 mL), brine and dried overNa₂SO₄ and evaporated to dryness. The crude material was purified bycolumn chromatography using silica gel (60-120 mesh) and pet ether/EtOAcas eluent to yield I-J tert-Butyl2-(4-fluorophenyl)cyclopropanecarboxylate [56.0 g g; yield 52%] as awhite solid.

HPLC: 97.2% (AUC), Rt 5.56 min. Method: A—0.1% TFA in H2O, B-0.1% TFA inACN, Flow 2.0 mL/min, Column: XBridge C8 (50×4.6 mm, 3.5 μm).

LCMS: 98.8% (AUC), Rt 6.99 min, MS(ES⁻) 179.0. Method: A: 10 mM NH₄HCO₃in H2O, B: ACN, Flow 1.0 mL/min, Column: XBridge C8 (50×4.6 mm, 3.5 μm).

¹H NMR (DMSO-d₆, 400 MHz) δ 7.20-7.10 (m, 2H), 7.09-7.05 (m, 2H),2.49-2.33 (m, 1H), 1.82-1.77 (m, 1H), 1.40 (s, 9H), 1.39-1.36 (m, 1H),1.30-1.20 (m, 1H).

Step 9: Preparation of I-9

Under N₂, tert-butyl 2-(4-fluorophenyl)cyclopropanecarboxylate (12.0 g;50.79 mmol; 1.00 eq.) was dissolved in DCM (60 mL). 4M HCl in dioxane(38.1 mL) was added. After stirring for 6 hr. at RT an HPLC indicated65% conversion. More HCl in dioxane (20 mL) was added and the reactionwas stirred O/N at RT after what an HPLC indicated full conversion and100% a/a. The reaction mixture was evaporated to dryness at RT (firstremoved excess HCl) then turned the bath on at ET=50° C. to remove thesolvents to yield I-K tert-Butyl2-(4-fluorophenyl)cyclopropanecarboxylic acid [8.93 g g; yield 97%] as awhite solid as the expected racemic compound.

HPLC: 98.0% (AUC), Rt 3.55 min. Method: A—0.1% TFA in H2O, B—0.1% TFA inACN, Flow 2.0 mL/min, Column: XBridge C8 (50×4.6 mm, 3.5 μm).

1H-NMR (300 MHz, DMSO-d6) δ 12.2-10.6 (bs, 1H), 7.15-7.05 (m, 2H),7.05-6.95 (m, 2H), 2.61 (m, 1H), 1.88 (m, 1H), 1.67 (m, 1H), 1.39 (m,1H).

Step 10: Preparation of I-10

Chiral separation of I-K (10.2 g) was performed under the belowconditions:

Chiralpak AD-H, 250×20 mm, 5 μm; Heptane/EtOH (90/10); Concentration 83mg/mL; Flow 10 mL/min

to yield the 1st eluting, 1-L (1R, 2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid 5.0 g; yield 49%] as a white solid.

HPLC: 99.9% (AUC), Rt 3.1 min. Method: A—0.1% TFA in H₂O, B-0.1% TFA inACN, Flow 2.0 mL/min; Column: XBridge C8 (50×4.6 mm, 3.5 μm)

UPLC/MS: 98.5% (AUC), Rt 0.7 min, MS(ES⁻) 179. Method: A: water NH₄OAc10 mM; B-ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18 (2.1×50 mm,1.7 μm).

¹H NMR (CDCl₃, 300 MHz) δ 7.26-6.95 (m, 4H), 2.62-2.55 (m, 1H),1.88-1.62 (m, 2H), 1.40-1.26 (m, 1H).

Comments: The single crystal structure resolution gave as absoluteconfiguration the following (1R, 2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid.

Step 11: Preparation of Example 97

A solution of[R)-Cyclopropyl-(4-difluoromethoxy-phenyl)-methyl]-pyridazin-3-ylmethyl-amine(5.50 g; 18.01 mmol; 1.00 eq.) in DCE (110.00 mL) was cooled to 0° C.Then iPr₂NEt (6.13 mL; 36.03 mmol; 2.00 eq.) was added followed by(1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid (3.57 g; 19.82mmol; 1.10 eq.). The reaction mixture was stirred at 0° C. for 15 minand then 2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane2,4,6-trioxide (21.43 mL; 36.03 mmol; 2.00 eq.) was added dropwise(addition took 15 min). The cooling bath was removed and the mixture washeated to 60° C. (external temperature) for 5 hr. until completion. Thereaction mixture was cooled to RT, quenched with a saturated solution ofNaHCO₃ (100 mL) and phases were separated. The aqueous phase wasextracted with EtOAc (2×150 mL), combined organics were washed with asaturated solution of NaHCO₃ (100 mL), brine (100 mL), dried over MgSO₄,filtered and concentrated under reduced pressure giving a brown oilm=9.07 g. The crude product was purified by flash chromatography (SiO₂)eluting with EtOAc-cHex 7:3 to afford(1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid as a stickybeige solid m=7.5 g, difficult to handle, NMR showed 1.7% of EtOAc andtraces of acetic acid.

HPLC: 99.1% (AUC), Rt 4.5 min. Method: A—0.1% TFA in H₂O, B-0.1% TFA inACN, Flow 2.0 mL/min; Column XBridge C8 (50×4.6 mm, 3.5 μm).

Chiral HPLC (SFC): 100.0% (AUC), Rt 1.9 min. Method: CO2, EtOH, DIEA,Flow 4.0 mL/min, Column Chiralpak AYH (250×4.6 mm).

UPLC/MS: 98.1% (AUC), Rt 1.8 min, MS(ES⁺) 468. Method: A: water NH₄OAc10 mM; B—ACN, Flow-1.0 mL/min. Column: Acquity UPLC BEH C18 (2.1×50 mm,1.7 μm).

An alternative procedure was used on small scale:

Acid chloride 1-10 (300 mg, 1.51 mmol) was added to a solution (1.25 M)of amine 1-4 (300 mg, 0.98 mmol) in pyridine at RT under N₂ atmosphereand stirred overnight (˜20 h). The reaction was diluted with diethylether (50 mL) and washed with H₂O (30 mL×2), aqueous NH₄Cl (30 mL),aqueous NaHCO₃ (30 mL) and brine (15 mL). The organic layer was dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography (small silica gel column 2.5×7 cm,eluant=1/1 hexane/diethyl ether (300 mL) to pure diethyl ether (400 mL))to provide Example 97 as a very thick, light-brown oil (247 mg, 54%yield, 98% purity). LCMS (Method 2) 468.2 (M+H)⁺.

¹H NMR (CDCl₃, 300 MHz) δ 9.03-8.95 (m, 1H), 7.65-6.87 (m, 10H), 6.49(t, J=73.8 Hz, 1H), 5.26-4.30 (m, 4H), 2.52-2.46 (m, 1H), 1.94-1.57 (m,2H), 1.390-1.10 (m, 2H), 0.87-0.05 (m, 3H).

Determination of Absolute Stereochemistry:

Trials of recrystallization were performed in order to get crystallineform. Different solvents or mixtures were tried to recrystallize theparent on 150 mg scale (2-BuOH, Et₂O/pentane, Et₂O, MIBK, 1-BuOH,DCM/pentane, ACN/H₂O, ACN, MTBE, diisopropylether, heptanone,diphenylether, AcOH, AcOH/H₂O, toluene, dibutylether). Finally after 2weeks, recrystallisation from dibutylether occurred to afford crystals.XRPD showed crystalline form and structure was resolved via singlecrystal XRay analysis.

5.0 g of the beige sticky solid previously isolated was taken up indibutyl ether (125 mL), the reaction mixture was heated until completedissolution and then the oil bath was removed. Under stirring, seeding(100 mg of crystals of the smaller batch) was performed andcrystallization occurred after a few minutes. The suspension was stirredfor 5 hr. at RT and then it was put in the fridge for 2 days. Thesuspension was filtered, washed with dibutylether (50 mL) and driedunder reduced pressure to yield(1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-cyclopropyl-(4-difluoromethoxy-phenyl)-methyl]-pyridazin-3-ylmethyl-amide[4.1g; yield 84%; corrected yield 73%] as an off white solid. XRPD showed adifferent crystalline form than the smaller batch (see FIG. 1).

Example 98: (1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(S)-cyclopropyl-(4-difluoromethoxy-phenyl)-methyl]-pyridazin-3-ylmethyl-amide

Intermediate bs (96 mg, 0.32 mmol), Intermediate eh (94 mg, 0.47 mmol)and triethylamine (0.125 mL, 0.90 mmol) were reacted in DCM according toGeneral Procedure C to give the title compound as a light brown glassyoil (89 mg, 61%). LCMS (Method 2) 468.2 (M+H)⁺.

Example 99: (1R, 2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amide

Synthetic scheme for small scale synthesis (<5 g): (Note: synthesisdescribed gives is a mixture of two isomers (separation is discussedfollowing large scale synthesis).

Protocols:

Step 1: Preparation of 3-(ethylsulfanyl)benzaldehyde (II-1)

To a solution of 3-bromo-1-ethanesulfanylbenzene (3.000 g, 13.8 mmol) inanhydrous THF at −78° C. under a nitrogen atmosphere was added 1.963Mn-BuLi (7.742 ml, 15.2 mmol) dropwise and the mixture stirred at thistemperature for 5 min. After this time DMF (2.14 ml, 27.6 mmol) wasadded dropwise and the mixture allowed to attain ambient temperatureover 15 minutes. Once complete the reaction was poured into water (50ml) and the organic layer separated. The organics were again washed withwater (×1) and brine (×1) dried (MgSO₄), filtered and concentrated invacuo to give crude aldehyde. The aldehyde was purified by columnchromatography (silica-gel, 5% EtOAc/petroleum spirits, R_(f)=0.4 1/19EtOAc/PS) to yield 1.883 g, 82% of II-1 as a pale yellow oil. ¹HNMR (300MHz, CDCl₃) δ 9.98 (s, 1H), 7.79 (dd, J=1.5, 2.1 Hz 1H), 7.65 (ddd,J=1.2, 1.5, 7.5 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 3.02 (q, J=7.2 Hz, 2H),1.35 (t, J=7.5 Hz, 3H).

Step 2: Preparation of cyclopropyl[3-(ethylsulfanyl)phenyl]methanol(II-2)

To a stirred solution of II-1 (2.64 g, 15.9 mmol) in dry THF (20 ml) at0° C. under N₂ atmosphere was added cyclopropyl magnesium bromide (0.5 Min THF, 35 ml, 17.5 mmol) dropwise. The cold bath was removed and thereaction mixture stirred at room temperature for 30 min. TLC in 10%ethyl acetate in hexane indicated the disappearance of startingaldehyde. The reaction mixture was cooled to 0° C. and quenched withsat. NH₄Cl solution and extracted with 3×25 ml of diethyl ether. Theorganic extracts were combined, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica-gel, 5-25% EtOAc/petroleum spirits,R_(f)=0.3 1/4 EtOAc/PS) to afford II-2 (2.55 g, 77% yield) as a paleyellow oil. ¹HNMR (300 MHz, CDCl₃) δ 7.40-7.39 (m, 1H), 7.28-7.21 (m,3H), 3.99 (d, J=8.4 Hz, 1H), 2.97 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.5 Hz,3H), 1.26-1.17 (m, 1H), 0.66-0.36 (m, 4H).

Step 3: Preparation of cyclopropyl[3-(ethylsulfonyl)phenyl]methanol(II-3)

To a stirred solution of II-2 (2.54 g, 12.2 mmol) in dry DCM (20 ml) at00° C. under N₂ atmosphere was added m-CPBA (5.12 g, 26.0 mmol) in 3portions. The cold bath was removed and the reaction mixture stirred atroom temperature for 1 h. LCMS indicated the reaction complete. Thereaction was quenched with sat. NaHCO₃ solution and extracted with 3×25ml of ethyl acetate. The organic extracts were combined, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica-gel, 30-50%EtOAc/petroleum spirits, R_(f)=0.1 1/1 EtOAc/PS) to afford II-3 (2.81 g,96% yield) as a pale cloudy oil. ¹HNMR (300 MHz, CDCl₃) δ 7.99-7.98 (m,1H), 7.83 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 4.10 (d, J=8.4 Hz,1H), 3.13 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H), 1.21 (m, 1H), 0.66(m, 2H), 0.48 (m, 2H). MS (ES⁺) m/z 258.2 (M+NH₄ ⁺).

Step 4: Preparation of1-[azido(cyclopropyl)methyl]-3-(methylsulfonyl)benzene3-[azido(cyclopropyl)methyl]phenyl methyl sulfone (II-4)

To a stirred solution of II-3 (1.40 g, 5.8 mmol) in dry PhMe (15 ml) at00° C. under N₂ atmosphere was added DPPA (1.7 mL, 7.9 mmol) drop-wisefollowed by DBU (1.2 mL, 8.0 mmol) drop-wise. The cold bath was removedand the reaction mixture stirred at room temperature for 30 min beforeheating at 80° C. for 5 hours. LCMS indicated the reaction complete. Thereaction was quenched with sat. NH₄Cl solution and extracted with 3×25ml of ethyl acetate. The organic extracts were combined and washed withsat. NH₄Cl solution, H₂O (×2) and brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (silica-gel, 15-25% EtOAc/petroleum spirits,R_(f)=0.27 1/3 EtOAc/PS) to afford II-4 (1.45 g, 94% yield) as a clearoil.

NB: It is necessary to run a gradient elution as the azide runs justabove an impurity (R_(f)=0.21 1/3 EtOAc/PS) from the reaction. The azidedevelops as a green spot in vanillin dip, the impurity does not developusing these conditions. ¹HNMR (300 MHz, CDCl₃) δ 7.91 (dd, J=2.1, 3.0 Hz1H), 7.86 (ddd, J=1.5, 1.5, 7.8 Hz, 1H), 7.67 (ddd, J=7.8, 1.2, 1.2 Hz,1H), 7.58 (dd, J=7.8, 7.8 Hz, 1H), 3.95 (d, J=8.7 Hz, 1H), 3.13 (q,J=7.5 Hz, 2H), 1.29 (m, 4H), 0.82 (m, 1H), 0.64 (m, 2H), 0.38 (m, 2H).MS (ES⁺) m/z 283.3 (M+NH₄ ⁺).

Step 5: Preparation of1-cyclopropyl-1-[3-(ethylsulfonyl)phenyl]methanamine (II-5)

To a stirred solution of the II-4 (1.45 g, 5.5 mmol) in MeOH (15 ml)under N₂ atmosphere was added 10% Pd/C (136.7 mg, ˜9% w/w) in oneportion. The flask was evacuated and flushed with H_(2(g)) and thereaction mixture stirred at room temperature for 2 h. LCMS indicated thereaction complete. The reaction was filtered through Celite® andconcentrated under reduced pressure to afford II-5 (1.15 g, 88% yield)as a yellow oil. ¹HNMR (300 MHz, CDCl₃) δ 7.95 (dd, J=1.8, 1.8 Hz, 1H),7.76 (m, 2H), 7.53 (dd, J=7.8, 7.8 Hz, 1H), 3.29 (d, J=8.4 Hz, 1H), 3.12(q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H), 1.06 (m, 1H), 0.64 (m, 1H),0.51 (m, 1H), 0.34 (m, 2H). MS (ES⁺) m/z 479.2 (M+M⁺).

Step 6: Preparation of 1-cyclopropyl-1-[3-(ethylsulfonyl)phenyl]-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl} methanamine (II-6)

To a stirred suspension of II-5 (1.14 g, 4.8 mmol) and anhydrous MgSO₄(1.35 g, 11.2 mmol) in 1,2-DCE (30 ml) under N₂ atmosphere was6-(trifluoromethyl)nicotinaldehyde (854.7 mg, 4.8 mmol) in one portion.The reaction was stirred at room temperature for 30 min before additionof NaBH(OAc)₃ (1.49 g, 7.0 mmol) in one portion. The reaction wasstirred at room temperature for a further 3 h. LCMS indicated thereaction complete. The reaction was quenched with sat. NaHCO₃ solutionand extracted with 3×25 mL of ethyl acetate. The organic extracts werecombined, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was purified by column chromatography(silica-gel, 30-60% EtOAc/petroleum spirits, R_(f)=0.20 1/1 EtOAc/PS) toafford II-6 (1.69 g, 89% yield) as a pale yellow oil. ¹HNMR (300 MHz,CDCl₃) δ 8.60 (d, J=1.5 Hz, 1H), 7.94 (dd, J=1.5, 1.5 Hz, 1H), 7.8 (m,2H), 7.61 (m, 3H), 3.73 (q, J=), 3.77 (d, J=14.1 Hz, 1H_(a)), 3.70 (d,J=14.1 Hz, 1H_(b)), 2.96 (d, J=9 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.09(m, 1H), 0.66 (m, 1H), 0.45 (m, 1H), 0.31 (m, 2H). MS (ES⁺) m/z 399.2(M+H⁺).

Step 7: Preparation of (1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R/S)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amide(II-7)

To a stirred solution of II-6 (229.3 mg, 0.58 mmol) and 1-10 (124.4 mg,0.69 mmol) in 1,2-DCE (5 mL) at 0° C. under N₂ atmosphere was added TEA(160 μL, 1.1 mmol) followed by T3P (50% in EtOAc, 800 μL, 1.3 mmol)drop-wise. The cold bath was removed and the reaction mixture stirred atroom temperature for ˜16 hours. LCMS indicated the reaction complete.The reaction was quenched with sat. NaHCO₃ solution and extracted with3×5 ml of ethyl acetate. The organic extracts were combined, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica-gel, 5-20%EtOAc/DCM, R_(f)=0.48 3/17 EtOAc/DCM) to afford (1R,2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R/S)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amide(214.4 mg, 66% yield) as a glassy yellow oil. ¹HNMR (300 MHz, CDCl₃) δ8.64-8.43 (m, 1H), 7.96-7.39 (m, 6H), 7.07-6.72 (m, 4H), 5.37-4.35 (m,3H), 4.12 (q, J=7.2 Hz, 2H), 3.15-0.32 (m, 12H). MS (ES⁺) m/z 561.3(M+H⁺).

Synthetic Scheme for Large Scale Synthesis (25 g):

Protocols

Step 1-2: Preparation of cyclopropyl [3-(ethylthio) phenyl]methanone(Int. am)

Method as previously described.

UPLC/MS: 95.0% (AUC), Rt 1.13 min, MS(ES⁺) (239). Method: A: waterNH₄OAc 10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18(2.1×50 mm, 1.7 μm)

¹H NMR (DMSO, 300 MHz) δ 8.50-8.45 (m, 2H), 8.24-8.19 (m, 1H), 7.95-7.88(m, 1H), 3.50-3.42 (m, 2H), 3.10-3.00 (m, 1H), 1.22-1.12 (m, 7H).

Step 3: Preparation of 1-cyclopropyl-1-[3-(ethylsulfonyl)phenyl]-N-{[6-(trifluoromethyl) pyridin-3-yl]methyl} methanamine (II-6)

To a 100 mL three necked flask under nitrogen containing cyclopropyl[3-(ethylsulfonyl) phenyl] methanone 1-0 (5.00 g; 20.98 mmol; 1.00 eq.)in solution in dry THF (50 mL, 10V) was added5-(Aminomethyl)-2-(trifluoromethyl) pyridine, I-P (4.43 g; 25.18 mmol;1.20 eq.) and tetraethyl orthotitanate (17.73 mL; 83.93 mmol; 4.00 eq.)in one portion. Reaction mixture was stirred at reflux for 6 h untilcompletion (a sample was treated with an excess of NaBH₄ at 5° C. beforeinjection in UPLC/MS). Reaction mixture was cooled down to 0° C. andNaBH₄ (1.59 g; 41.96 mmol; 2.00 eq.) was added portion wise over 5minutes. Reaction mixture was stirred at 0° C. for 1 h until reductioncompletion.

Reaction mixture was quenched with an excess of methanol added dropwise(important foaming) then resulting suspension was filtered and filtratewas concentrated until 30 mL was left. Sodium hydroxide 1N (100 mL) wasadded and resulting thick suspension was suspended in MTBE. Filtrationwas done and salts were washed with MTBE. Biphasic filtrate wasseparated and aqueous phase was extracted with MTBE. Combined organicphase was washed with water, dried over Na₂SO₄, filtered andconcentrated to give thick yellow oil which was purified by flashchromatography (SiO₂) eluting with (Heptane/ethyl acetate: 1/1) to givetitle product I-Q [5.35 g; crude yield: 64%; purity: 94%; correctedyield: 60%] as yellow clear oil. Used without further purification

UPLC/MS: 94.0% (AUC), Rt 1.72 min, MS(ES⁺) (399). Method: A: waterNH₄OAc 10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18(2.1×50 mm, 1.7 μm)

¹H NMR (300 MHz, CDCl3) δ 8.40-8.35 (d, J=2.0 Hz, 1H), 7.74-7.70 (m,1H), 7.65-7.55 (m, 2H), 7.50-7.44 (m, 1H), 7.43-7.38 (d, J=8.0 Hz, 1H),7.37-7.28 (m, 1H), 3.59-3.42 (m, 2H), 2.95-2.84 (m, 2H), 2.78-2.69 (d,J=8.9 Hz, 1H), 1.14-0.97 (m, 3H), 0.93-0.79 (m, 1H), 0.70-0.59 (m, 1H),0.49-0.36 (m, 1H), 0.28-0.16 (m, 1H), 0.15-0.00 (m, 1H).

Step 4: Preparation (1R, 2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylicacid[(R)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amide(Example 99)

To a 250 mL flask under nitrogen containing1-cyclopropyl-1-[3-(ethylsulfonyl)phenyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}methanamineI-Q (8.00 g; 20.08 mmol; 1.00 eq.) and(1R,2R)-2-(4-fluorophenyl)cyclopropanecarboxylic acid I-L (4.34 g; 24.09mmol; 1.20 eq.) in solution in 1,2-dichloroethane (120 mL; 15V) at 0° C.was added triethylamine (5.57 mL; 40.16 mmol; 2.00 eq.) in one portionfollowed by 1-propylphosphonic acid cyclic anhydride T3P (28.11 g; 44.17mmol; 2.20 eq.; 50% in ethyl acetate) which was added drop-wise over 5minutes. The cold bath was removed and the reaction mixture was stirredat 60° C. for 14 h until completion. Reaction mixture was cooled down to25° C. and quenched with a saturated solution of NaHCO₃. Phases wereseparated and aqueous phase was extracted with ethyl acetate. Combinedorganic phase was washed with a saturated solution of NaHCO₃, then withbrine. After drying over Na₂SO₄, filtration and concentration (bathtemp: 37° C.), title product 7 [11.36 g; crude yield: quantitative;purity: 93.7%; corrected yield 93.7%] was obtained as white solid foam.Chiral purification by SFC was done directly without furtherpurification using the conditions below: Column: Chiralcel OD-H, 250×20mm, 5 um; Co-solvent: 20% MeOH; Flow: 80 mL/min; Back Pressure: 120bars; Column temperature: 30° C.

Results:

4.12 g of the title compound (Example 99) and 4.24 g of the seconddiastereoisomer, Example 100, were obtained as respectively first andsecond eluting, after injection of 11.2 g of racemic mixture.

HPLC: 98.87% (AUC), Rt 5.01 min. Method: A—0.1% TFA in H₂O, B-0.1% TFAin ACN, Flow 2.0 mL/min; Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Chiral HPLC: 100.0% (AUC), Rt 7.7 min. Method: Hexane/IPA/DIEA90/10/0.1, Flow 2.0 mL/min, Column: Chiralcel OD (250×4.6 mm, 5 μm).

UPLC/MS: 100% (AUC), Rt 2.11 min, MS(ES⁺) (561). Method: A: water NH₄OAc10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18 (2.1×50 mm,1.7 μm)

¹H NMR (300 MHz, DMSO) δ 8.28-8.07 (m, 1H), 7.69-7.62 (m, 1H), 7.60-7.47(m, 3H), 7.43-7.26 (m, 2H), 7.04-6.94 (d, J=8.6 Hz, 1H), 6.90-6.81 (d,J=8.2 Hz, 1H), 6.78-6.63 (m, 2H), 4.88-4.59 (m, 2H), 4.54-4.23 (m, 1H),3.06-2.89 (m, 2H), 2.41-2.30 (m, 0.5H), 2.25-2.17 (m, 0.5H), 2.11-1.99(m, 0.5H), 1.85-1.71 (m, 0.5H), 1.45-1.15 (m, 2H), 1.03-0.86 (m, 1H),0.86-0.64 (m, 3H), 0.58-0.40 (m, 1H), 0.25-0.00 (m, 3H).

Absolute Configuration Determination

In order to establish absolute configuration of the asymmetric carbonbearing the nitrogen, racemic benzylamine intermediate II-5 (synthesisdescribed below) was synthesized and both enantiomers were separated bychiral HPLC. Then enantiomer II-5a was coupled with 4-bromobenzoic acidand structure of resulting amide II-9 was determined by X-ray to be the(R)-enantiomer, as described below. To provide further confirmation, the(S)-enantiomer II-5b was used to synthesize an analogue of the finalcompound, which was compared with pure Example 99 by chiral HPLC. Thestereochemistry of Example 99 was proved to be RRR.

Synthetic Scheme for Preparation of Heavy Atom-Containing Amide Analogueof II-5 for Crystallographic Determination of Absolute Stereochemistry.

Protocol

Step 1: Preparation ofC-Cyclopropyl-C-(3-ethylsulfanyl-phenyl)-methylamine hydrochloride(II-8)

To a 500 mL three necked flask under nitrogen containing3-Bromo-1-ethanesulfanylbenzene (20.00 g; 92.11 mmol; 1.00 eq) in drytoluene (200 mL; 20V) at RT was added rapidly a solution ofn-butyllithium (36.84 mL; 92.11 mmol; 1.00 eq; 2.5M in toluene).Reaction mixture was stirred at RT overnight (Monitoring oflithium-bromine exchange was performed by quenching a sample with CO₂and by injecting resulting carboxylic acid in UPLC/MS: 7% of startingmaterial 3 was left). Reaction mixture was stirred at 40° C. for 4 h toget lithium-bromine exchange completion.

Temperature was brought down to −30° C. and cyclopropanecarbonitrile(7.64 mL; 101.32 mmol; 1.10 eq) was added drop wise over 10 minutes.Resulting nice orange light suspension was stirred at −30° C. for 2 hand was then allowed to warm up to 0° C. until completion (Monitoring ofreaction was done by quenching sample with HCl (1N) and followingketimine and ketone formation by UPLC/MS).

Ethanol (100 mL; 5V) was added in one portion and sodium borohydride(6.97 g; 184.22 mmol; 2.00 eq) was added to the resulting colourlesssolution keeping temperature below 10° C. Reaction mixture was stirredat RT over the week-end after what new batch of sodium borohydride (6.97g; 184.22 mmol; 2.00 eq) was added to get completion after 5 h.

Reaction mixture was poured in a large beaker containing HCl5N (100 mL;careful important foaming). Phases were separated and aqueous phase waswashed with MTBE (2×150 mL) and then basified with NaOH5N. Aqueous phasewas then extracted with MTBE (3×150 mL) and combined organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated toafford colourless oil (m=12.05 g)

This oil was dissolved in 250 mL of diethyl ether at RT and then HCl2Nin diethyl ether was added drop wise. Resulting white suspension wasfiltered and dried under reduced pressure to give title product II-8[14.21 g; crude yield: 63%; purity: 100%; corrected yield 63%] as whitepowder.

UPLC/MS: 100% (AUC), Rt 1.00 min, MS(ES⁺) (207 [M-NH₂]⁺). Method: A:water NH₄OAc 10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18(2.1×50 mm, 1.7 μm)

Step 2: Preparation ofC-Cyclopropyl-C-(3-ethanesulfonyl-phenyl)-methylamine (II-5)

To a solution of II-8 (12.00 g; 49.22 mmol; 1.00 eq) in acetic acid (120mL; 10V) was added perchloric acid (4.20 mL; 49.22 mmol; 1.00 eq; 70%)in one portion. Then reaction mixture was cooled down to 15° C. andhydrogen peroxide (50.27 mL; 492.21 mmol; 10.00 eq; 30%) was added dropwise over 10 min (exothermic at the beginning of addition) keepingtemperature at 20° C. Then solution was stirred at RT for 15 min afterwhat exotherm brought temperature at 30° C., ice bath was used tomaintain temperature at 25° C. for 5 h until nearly completion.

Quench was done with an excess of NaOH 5N and extraction was done withdichloromethane. After drying over Na₂SO₄, filtration and concentration,resulting yellow oil (m=10 g) was purified by chromatoflash (SiO₂, THF)to give title product II-5 [8.00 g; crude yield: 68%; purity: 91%;corrected yield 62%] as colourless oil (traces of THF by NMR).

UPLC/MS: 91% (AUC), Rt 0.57 min, MS(ES⁺) (239 [M-NH₂]⁺). Method: A:water NH₄OAc 10 mM; B—ACN, Flow 1.0 mL/min. Column: Acquity UPLC BEH C18(2.1×50 mm, 1.7 μm)

Step 3: Chiral Separation

Chiral separation was done on Chiralpak AY-H, 250×20 mm, 5 um usingHeptane/EtOH/DEA (60/40/0.1) as eluent (feed concentration: 114 mg/mL;flow 10 mL/min). First eluting enantiomer II-5a (m=3.00 g) and secondeluting enantiomer II-5b (m=3.47 g) were obtained.

First eluting enantiomer was arbitrary selected for next step

Step 4: Preparation of4-Bromo-N—[(R)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-benzamide(II-9)

To a stirred solution of II-5a (289 mg; 1.21 mmol; 1.00 eq) and4-bromo-benzoic acid I-U (291.28 mg; 1.45 mmol; 1.20 eq) in DCE (4.00mL) at RT under was added triethylamine (0.33 mL; 2.42 mmol; 2.00 eq) inone portion followed by2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (1.69g; 2.66 mmol; 2.20 eq; 50% in ethyl acetate). The reaction mixture wasstirred at RT until completion.

Reaction mixture was washed successively with a saturated solution ofNaHCO₃, HCl (1N), water and finally with brine. After drying overNa₂SO₄, filtration and concentration, resulting off white solid wassuspended in diethyl ether, filtered and dried to give title productII-9 [320 mg; crude yield: 63%; purity: 98%; corrected yield 62%] as offwhite solid. This product was sent for absolute configurationdetermination

a. Results

Crystal structure (see FIG. 2) was solved and showed undoubtedly theR-configuration. Therefore first eluting enantiomer II-5a was R andsecond eluting enantiomer II-5b was S.C—[(S)—C-Cyclopropyl-C-(3-ethanesulfonyl-phenyl)]-methylamine. II-5b wasthen used for the synthesis depicted below:

Resulting (1R, 2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(S)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amide(II-10) was injected by chiral SFC in the same conditions than the oneused for the isolation of Example 99 (Chiralcel OD-H, 250×20 mm, 5 um;Co-solvent: 20% MeOH). Under these conditions Example 99 was the firsteluting and product II-10, showed to be the second eluting Example 100(SRR).

Therefore absolute configuration of the Example 99 could be definitivelyattributed as RRR.

Example 100: (1R, 2R)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(S)-cyclopropyl-(3-ethanesulfonyl-phenyl)-methyl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amide

Separated from a diastereomeric mixture II-7. Column: Chiralcel OD-H,250×20 mm, 5 um; Co-solvent: 20% MeOH; Flow: 80 mL/min; Back Pressure:120 bars; Column temperature: 30° C. (Second eluting isomer, 5.01 min).UPLC/MS (Method 3) 560.6 (M+H).

Example 101: 2-(4-Fluorophenylsulfonyl)-N-(2-phenylpropan-2-yl)-N-(pyridine-2-ylmethyl)acetamide

Pyridine-2-carboxaldehyde (33 μL, 0.37 mmol) and 2-phenylpropane-2-amine(53 μL, 11.35 mmol), were reacted according to General Procedure L toafford 2-Phenyl-N-(pyridine-2-ylmethyl)propane-2-amine as a light brownoil. MS (ES⁺) m/z 227.3 (M+H)⁺.2-Phenyl-N-(pyridine-2-ylmethyl)propane-2-amine (50 mg, 0.22 mmol),Intermediate dm (58 mg, 0.27 mmol), T3P (0.265 mL, 0.44 mmol) andtriethylamine (0.037 mL, 0.27 mmol) were reacted according to GeneralProcedure D to give the title compound as a pale yellow solid (75 mg,79%). LCMS (Method 2) 427.2 (M+H)⁺.

The remaining examples are described in Tables 3-12. It will beunderstood that the R₁₀ groups installed during the reductive aminationsdescribed in General Procedures A, B, K, L, Y, AD resulting from thecorresponding commercially available amine, aldehyde or ketone unlessotherwise specified. The R₁₀ groups in these tables are identifiedbelow:

LCMS conditions in Tables 3-12 are denoted as: ^(a) LCMS (Method 2) and^(b) UPLC (Method 3).

TABLE 3

Chiral Separation SFC/ MS LCMS RT HPLC # of Example R₁ R₃ R₁₀ R₁₁ R₁₂Int. i Int. ii Procedures [M + H] (min.) cond. iso. 110 4-OCHF₂ iPr b4′-F — bm ea Gen. A, C 487.3 ^(a) 1 111 4-OCHF₂ iPr b 4′-F — bn ea Gen.A, C 487.3 ^(a) 1 112 4-OCHF₂ iPr ag 4′-F — bm ea Gen. A, C, R 503.3^(a) 1 113 4-OCHF₂ iPr a 4′-F — bn ea Gen. A, C 470.2 ^(a) 1 114 4-OCHF₂iPr a 4′-F — bm ea Gen. A, C 470.2 ^(a) 1 115 4-OCHF₂ iPr b 2′-F 4′-F bmeb Gen. A, C 505.2 ^(a) not separated 2 116 4-SO₂Et Et b 4′-F — bc eaGen. A, C 499.2 ^(a) not separated 2 117 4-SO₂Et Et b 4′-F — bd ea Gen.A, C 499.2 ^(a) not separated 2 118 4-SO₂Et Et a 4′-F — bd ea Gen. A, C482.2 ^(a) not separated 2 119 4-SO₂Et Et d 2′-F 4′-F bc eb Gen. A, C567.3 ^(a) not separated 2 120 4-SO₂Me Et d 4′-F — be ea Gen. A, C 535.1^(a) 1 121 4-SO₂Me Et d 4′-F — bf ea Gen. A, C 535.2 ^(a) 1 122 4-SO₂MeEt b 4′-F — bf ea Gen. A, C 485.2 ^(a) 1 123 4-SO₂Me Me a 4′-F — bh eaGen. A, C 454.2 ^(a) 1 124 4-SO₂Me Et a 4′-F — bf ea Gen. A, C 468.1^(a) 1 125 4-SO₂Me Et a 4′-F — be ea Gen. A, C 468.2 ^(a) 1 126 4-SO₂MeMe d 4′-F — bg da Gen. A, D 521.3 ^(a) 1 127 4-SO₂Me Et d 2′-F 4′-F bedb Gen. A, D 553.3 ^(a) not separated 2 128 4-SO₂Me Et d 2′-F 4′-F bf ebGen. A, C 553.6 ^(b) 32.15 F 1 129 4-SO₂Me Et d 2′-F 4′-F bf eb Gen. A,C 553.6 ^(b) 27.33 F 1 130 4-SO₂iPr Et a 4′-F — fa ea Gen. S, A, M 496.3^(a) not separated 2

TABLE 4

Chiral Separation Silica Gel F-C MS LCMS RT or SFC/HPLC # of Example R₁R₂ R₁₀ Int. i Procedures [M + H] (min.) cond. iso. 140 4-OCHF₂ — s aiGen. A, C, N, Q 517.3 ^(a) 2 141 4-OCHF₂ — b ai Gen. A, C, N 528.3 ^(a)1.866 Silica Gel F-C 1 142 4-OCHF₂ — b ai Gen. A, C, N, Q 542.3 ^(a)1.832 Silica Gel F-C 1 143 3-SO₂Et — b fh Gen. A, C, O, Q 568.2 ^(a) 1144 4-F 2-F b fi Gen. A, C 512.3 ^(a) 1 145 4-F 2-F c fi Gen. A, C 512.3^(b) 4.42 D 1 146 3-CF₃ — b fb Gen. S, A, C, O, Q 544.2 ^(a) 2.423Silica Gel F-C 1 147 3-CF₃ — b fb Gen. S, A, C, O, Q 544.2 ^(a) 2.391Silica Gel F-C 1 148 3-CF₃ — q fb Gen. S, A, C, O, Q 544.2 ^(a) 2.195Silica Gel F-C 1

TABLE 5

LCMS RT MS [M + H]⁺ (min.) Example R₁ R₁₅ R₁₀ Int. i Procedures (Method2) (Method 2) 150 4-OCHF₂ Me c ah Gen. A, C, N, Q 514.2 1.916 1514-OCHF₂ Me c ah Gen. A, C, N, Q 514.2 5.023 152 4-OCHF₂ H b ah Gen. A,C, N 500.3 2.205 153 4-OCHF₂ H b ah Gen. A, C, N 500.3 2.180 154 4-OCHF₂Me b ah Gen. A, C, N, Q 514.2 2.200 155 4-F Me c ag Gen. A, C, N, Q466.2 1.936 156 4-F Me c ag Gen. A, C, N, Q 466.2 1.589 157 4-F H c agGen. A, C, N 452.2 1.809 158 4-F H b ag Gen. A, C, N 452.2 2.026 1594-OCF₃ Me b at Gen. A, C, N, Q 532.3 2.128 160 4-OCHF₂ Me af ah Gen. A,C, N, Q 564.3 2.052 161 4-OCHF₂ Me af ah Gen. A, C, N, Q 564.3 2.147 1624-OCF₃ Me q at Gen. A, C, N, Q 532.3 2.216 163 4-OCF₃ Me q at Gen. A, C,N, Q 532.3 2.080 Note: Examples in table are single isomers seperatedfrom diastereometic mixtures after General Procedure C by Silica GelFlash

TABLE 6

Chiral Separation Silica Gel F-C MS LCMS RT or SFC/HPLC # of Example R₁n R₁₀ Int. i Procedures [M + H] (min.) cond. iso. 170 3-SO₂Et 2 c awGen. A, C 555.2 ^(a) not separated 2 171 4-F 1 c gh Gen. A, D 467.5 ^(b) 2.16 A 1 172 4-F 1 c gh Gen. A, D 467.5 ^(b)  2.57 A 1 173 4-F 1 a ghGen. A, D 450.5 ^(b) 27.03 F 1 174 4-F 1 a gh Gen. A, D 450.5 ^(b) 34.12F 1 175 4-F 1 b gh Gen. A, C 467.3 ^(b) 3.022 Silica Gel F-C 1 176 4-F 1b gh Gen. A, C 467.3 ^(b) 2.837 Silica Gel F-C 1

TABLE 7

Chiral Separation MS LCMS RT SFC/HPLC # of Example R₁ R₁₀ R₁₁ R₁₂ Int. iInt. II Procedure [M + H] (min.) cond. iso. 180 4-OCHF₂ a 3′-F 4′-F btec Gen. A, M 486.2 ^(a) not separated 2 181 4-OCHF₂ a 3′-F 4′-F bt ecGen. A, M 486.2 ^(b) 3.54 A 1 182 4-OCHF₂ a 2′-F 4′-F bt eb Gen. A, M486.2 ^(b) 4.57 A 1 183 4-OCHF₂ k 4′-F — bt ea Gen. A, C, O 456.2 ^(a) 1184 4-OCHF₂ a 3-CF₃ — bt ed Gen. A, C 518.1 ^(b) 1.91 A 1 185 4-OCHF₂ r4′-F — ak ea Int. fc, Gen. C 523.2 ^(a) not separated 2 186 4-OCHF₂ r4′-F — ak ea Int. fc, Gen. C 523.2 ^(b) 8.2 C 1 187 4-OCHF₂ y 4′-F — btea Gen. A and C 470.2 ^(a) 1 188 4-OCHF₂ a 2-OCF₃ — bt ef Gen. A, M534.2 ^(a) not separated 2 189 4-OCHF₂ z 4′-F — bt ea Gen. A, C 470.2^(a) 1 190 4-OCHF₂ aa 4′-F — bt da Gen. A, D 470.2 ^(a) 1 191 3-SO₂Et m4′-F — am ea Int. ac, Gen. C 543.2 ^(a) not separated 2 192 3-SO₂Et ab4′-F — am ea Gen. K, C 494.2 ^(a) not separated 2 193 3-SO₂Et b 2′-F4′-F ca eb Gen. A, C 529.6 ^(b) 32.7 E 1 194 3-SO₂Et b 2′-F 4′-F ca ebGen. A, C 529.6 ^(b) 25.72 E 1 195 3-SO₂Et b 2′-F 4′-F cb eb Gen. A, C529.6 ^(b) 5.65 B 1 196 3-SO₂Et b 2′-F 4′-F cb eb Gen. A, C 529.6 ^(b)4.15 B 1 197 3-SO₂Et b 3′-F 4′-F cb ec Gen. A, C 529.6 ^(b) 5.57 B 1 1983-SO₂Et b 3′-F 4′-F cb ec Gen. A, C 529.6 ^(b) 3.67 B 1 199 3-SO₂Et b3′-F 4′-F ca ec Gen. A, C 529.6 ^(b) 22.83 F 1 209 3-SO₂Et b 3′-F 4′-Fca ec Gen. A, C 529.6 ^(b) 15.87 F 1 210 3-SO₂Et b 3′-CF₃ — cb ed Gen.A, C 561.6 ^(b) 2.92 B 1 211 3-SO₂Et b 3′-CF₃ — cb ed Gen. A, C 561.6^(b) 4.27 B 1 212 3-SO₂Et b 3′-CF₃ — ca ed Gen. A, C 561.6 ^(b) 28.25 B1 213 3-SO₂Et b 3′-CF₃ — ca ed Gen. A, C 561.6 ^(b) 35.35 B 1 2143-SO₂Et q 4′-F — ar ea Gen. A, C 511.2 ^(a) not separated 2 215 3-SO₂Etb 4′-F — ar ea Gen. A, C 511.6 ^(b) 2.55 B 1 216 3-SO₂Et e 3′-CF₃ — ared Gen. A, C 543.2 ^(a) not seperated 4 217 3-SO₂Et e 3′-CF₃ — ar edGen. A, C 543.6 ^(b) 22.39 J 1 218 3-SO₂Et c 4′-F — ar ea Gen. A, C511.2 ^(a) not separated 2 219 3-SO₂Et u 4′-F — ar ea Gen. A, M 520.2^(a) not separated 2 220 3-SO₂Et s 2′-OCF₃ — ca ef Gen. A, M 552.2 ^(a)not separated 2 221 3-SO₂Et s 2′-OCF₃ — cb ef Gen. A, M 552.2 ^(a) notseparated 2 222 3-SO₂Et b 4′-OCHF₂ — ar eg Gen. A, C 559.2 ^(a) notseparated 4 223 3-SO₂Et a 4′-F — ca ea Gen. A, C 494.2 ^(a) 1 2243-SO₂Et a 4′-F — cb ea Gen. A, C 487.3 ^(a) 1 225 3-SO₂Et a 3′-CF₃ — cbed Gen. A, M 544.2 ^(a) not separated 2 226 3-SO₂Et a 3′-CF₃ — ca edGen. A, M 544.2 ^(a) not separated 2 227 4-SO₂Et b 3′-CF₃ — bx ed Gen.A, C 561.6 ^(b) 3.05 B 1 228 4-SO₂Et b 3′-CF₃ — bx ed Gen. A, C 561.6^(b) 4.15 B 1 229 4-SO₂Et b 2′-F 4′-F bx eb Gen. A, C 529.6 ^(a) 4.42 D1 230 4-SO₂Et b 2′-F 4′-F bx eb Gen. A, C 529.6 ^(b) 5.21 D 1 2314-3O₂Et a 4′-F — bx ea Gen. A, C 494.2 ^(a) 1 232 4-3O₂Et b 4′-F — bx eaGen. A, C 511.2 ^(a) 1 233 4-SO₂Et b 4′-F — bw ea Gen. A, C 511.2 ^(a) 1234 4-SO₂iPr c 4′-F — by ea Gen. A, C 525.3 ^(a) 1 235 4-SO₂iPr c 4′-F —bz ea Gen. A, C 525.3 ^(a) 1 236 4-SO₂iPr a 4′-F — bz ea Gen. A, C 508.3^(a) 1 237 4-SO₂iPr a 4′-F — by ea Gen. A, C 508.3 ^(a) 1 238 4-SO₂iPr b4′-F — bz ea Gen. A, C 525.3 ^(a) 1 239 4-SO₂iPr b 4′-F — by ea Gen. A,C 525.3 ^(a) 1 240 3-SO₂iPr a 4′-F — by ea Gen. Y, M 508.3 ^(a) 1 2413-SO₂iPr a 4′-F — bu ea Gen. Y, M 508.3 ^(a) 1 242 3-SO₂iPr b 4′-F — buea Gen. A, C 525.3 ^(a) 1 243 3-3O₂iPr b 4′-F — by ea Gen. A, C 525.3^(a) 1 244 3-SO₂iPr q 4′-F — az ea Gen. K, C 525.3 ^(a) not separated 2245 3-SO₂iPr c 4′-F — bu ea Gen. A, C 525.3 ^(a) 1 246 3-SO₂iPr c 4′-F —by ea Gen. A, C 525.3 ^(a) 1 247 3-SO₂iPr ab 4′-F — az da Gen. K, D508.3 ^(a) not separated 2 248 4-SO₂cPr a 4′-F — cd ea Gen. A, C 506.2^(a) 1 249 4-SO₂cPr a 4′-F — ce ea Gen. A, C 506.2 ^(a) 1 250 4-SO₂cPr b4′-F — cd ea Gen. A, C 523.2 ^(a) 1 251 3-CN c 4′-F — * da Gen. A, D444.1 ^(b) 32.4 H 1 252 3-CN c 4′-F — * da Gen. A, D 444.1 ^(b) 22.82 H1 253 4-Cl ac 4′-F — br da Gen. A, D, T 527.2 ^(a) 1 254 4-Cl ad 4′-F —br da Gen. A, D, T 481.2 ^(a) 1 (Step 1) 255 4-Cl ac 4′-F — br da Gen.A, D, T 513.3 ^(a) 1 * 3-(aminocyclopropylmethyl)-benzonitrilie

TABLE 8

Chiral Separation LCMS MS RT SFC/HPLC # of Example R₁ R₂ R₃ R₁₀ R₁₁ Int.i Int. ii Procedures [M + H] (min.) cond. iso. 260 4-OCHF₂ — cPr a 2′CF₃bt ek Gen. A, M 520.2 ^(b) 15.6 G 1 261 4-OCHF₂ — cPr a 2′CF₃ bt ek Gen.A, M 520.2 ^(b) 20.2 G 1 262 4-OCHF₂ — cPr a 4′-F ak ei Gen. A, M 470.2^(a) 1 263 4-OCHF₂ — cPr d 2′-SO₂Me bs dj Gen. A, D 597.3 ^(a) notseparated 2 264 4-SO₂iPr — cPr b 4′-F bz ei Gen. A, C 527.2 ^(a) 1 2653-SO₂Et — cPr b 2′-CF₃ cb ek 563.6 ^(b) 36.5 F 1 266 3-SO₂Et — cPr b2′-CF₃ cb ek 563.6 ^(b) 29.5 F 1 267 3-SO₂Et — cPr b 2′-CF₃ ca ek 563.6^(b) 6.56 B 1 268 3-SO₂Et — cPr b 2′-CF₃ ca ek 563.6 ^(b) 5.22 B 1 2694-SO₂Et — cPr b 2′-CF₃ an ek Gen. A, C 563.3 ^(a) 2.94 1 270 4-F —

b 4′-F gh oo Gen. A, C 469.5 ^(b) 1.1 I 1 271 4-F 2-F

b 4′-F fi di Gen. A, D 514.2 ^(a) not separated 2 272 4-Cl — cPr o 4′-Fbr ei Gen. A, C, R 453.3 ^(a) 1

TABLE 9

Chiral Separation LCMS SFC/ MS RT HPLC Example R₁ R₂ R₃ R₁₀ R₁₁ R₁₂ R₁₃Int. i Int. ii Procedures [M + H] (min.) cond. 280 4-Cl — Me h H H 4′-F{circumflex over ( )} dm Gen. A, D 479.2 ^(a) 281 4-OCHF₂ — CH₂OMe d H H— fj dl Gen. A, D 560.2 ^(a) 282 4-F —

d H H — gh dl Gen. A, D 537.1 ^(b) 4.9 A 283 4-F — iPr v H H 4′-F bl dmGen. A, D 479.2* ^(a) 284 4-F — iPr x H H 4′-F bl dm Gen. A, C, O 479.2^(a) 286 4-F 2-F

b H H 4′-F fi dm Gen. A, D 550.1 ^(b) 5.87 B 287 4-F 2-F

b H H 4′-F fi dm Gen. A, D 550. 1 ^(b) 4.48 B 288 4-SO₂Me — Me d Me Me —bg ep Gen. A, E 569.3 ^(a) * Note: MS shown as M —CO₂C(CH₃) + H{circumflex over ( )} 4-chloro-(R)-a-methyl-benzenemethanamine Allexamples are single isomers

TABLE 10

Chiral Separation Silica Gel F-C LCMS or SFC/ MS RT HPLC # of Example #R₁ R₁₀ R₁₁ R₁₂ R₁₃ Int. ii Int. ii Procedures [M + H] (min.) cond. iso.290 4-Cl b H H 4′-F br dm Gen. A, D 491.2 ^(a) 1 291 4-Cl n H H 4′-F brdm Gen. A, D 491.2 ^(a) 1 292 4-Cl o H H 3′-CF₃ br dr Gen. A, D, R 539.2^(a) 1 293 4-Cl e H H 3′-CF₃ bq dr Gen. A, D 523.2 ^(a) 1 294 4-Cl e H H3′-CF₃ br dr Gen. A, D 523.2 ^(a) 1 295 4-Cl w H H 4′-F br dm Gen. A, D503.3 ^(a) 1 296 4-Cl e Me H 4′-F br eo Gen. A, M 487.3 ^(b) 7.42 B 1297 4-Cl e Me H 4′-F br eo Gen. A, M 487.3 ^(b) 4.93 B 1 298 4-OCHF₂ g HH 4′-F ak dm Gen. A, D 497.2 ^(a) not separated 2 299 4-OCHF₂ d H H 2′-Fbt dn Gen. A, D 573.3 ^(a) 1 300 4-OCHF₂ d H H 2′-F bs dn Gen. A, D573.3 ^(a) 1 301 4-OCHF₂ d H H — bt dl Gen. A, D 555.2 ^(a) 1 3024-OCHF₂ d H H — bs dl Gen. A, D 555.2 ^(a) 1 303 4-OCHF₂ c H H — bt dlGen. A, D 505.2 ^(a) 1 304 4-OCHF₂ c H H — bs dl Gen. A, D 505.2 ^(a) 1305 4-OCHF₂ a H H — bt dl Gen. A, D 488.3 ^(a) 1 306 4-OCHF₂ a H H — bsdl Gen. A, D 488.3 ^(a) 1 307 4-OCHF₂ a H H 3′-CF₃ bt dr Gen. A, D 556.3^(a) 1 308 4-OCHF₂ a Me Me 4′-F bt dq Gen. A, D 534.2 ^(a) 1 309 4-OCHF₂c H H 4′-F bt dm Gen. A, D 523.3 ^(a) 1 310 4-OCHF₂ a H H 3′-CF₃ bs drGen. A, D 556.3 ^(a) 1 311 4-OCHF₂ a Me Me 4′-F bs dq Gen. A, M 534.2^(a) 1 312 4-OCHF₂ d H H 4′-F ak dm Gen. A, D 573.1 ^(b) 1.8  B 1 3134-OCHF₂ d H H 4′-F ak dm Gen. A, D 573.1 ^(b) 2.57 B 1 314 4-OCHF₂ e H H4′-F ak dm Gen. A, D 505.2 ^(a) not separated 2 315 4-OCHF₂ u H H 4′-Fak dm Gen. A, D 532.3 ^(b) 6.91 I 1 316 4-OCHF₂ u H H 4′-F ak dm Gen. A,D 532.3 ^(b) 4.07 I 1 317 4-OCHF₂ s H H 4′-F ak dm Gen. A, D 496.3 [M −H] ^(a) not separated 2 318 4-OCHF₂ e Me Me 4′-F ak dq Gen. A, C 533.1^(b) 5.9  A 1 319 4-OCHF₂ e Me Me 4′-F ak dq Gen. A, C 533.1 ^(b) 3.63 A1 320 4-OCHF₂ f H H 4′-F bt dm Gen. A, D 519.2 ^(a) 1 321 4-OCHF₂ f H H4′-F bs dm Gen. A, D 519.2 ^(a) 1 322 4-OCHF₂ ae H H — bt dl Gen. A, D501.2 ^(a) 1 323 4-OCHF₂ ae H H — bs dl Gen. A, D 501.2 ^(a) 1 3244-OCHF₂ d Me Me — bs dp Gen. A, D 583.3 ^(a) 1 327 3-SO₂Et c H H — ar dlGen. A, D 531.2 ^(a) not separated 2 328 3-SO₂Et e Me Me — ar ep Gen. A,E 541.3 ^(a) not separated 2 329 2-OCH₂CHF₂ e H H 4′-F ax em Gen. A, C519.1 ^(b) 3.59 A 2 330 2-OCH₂CHF₂ d H H 4′-F ax dm Gen. A, D 587.3 ^(b)5.43 A 1 331 2-OCF₃ f H H 4′-F ay dm Gen. A, D 537.3 ^(b) 5.03 A 1 3323-CN d H H 4′-F * dm Gen. A, D 532.1 ^(b) 4.47 B 1 333 3-CN d H H 4′-F *dm Gen. A, D 532.1 ^(b) 3.81 B 1 * 3-(aminocyclopropylmethyl)-benzonitrile

TABLE 11

MS [M + H] Example R₁₀ R₁₁ Int. ii Procedures (Method 2) 340 d 4′-F dmGen. A, D 511.2 341 d H dl Gen. A, D 493.2 342 f 4′-F dm Gen. A, D 457.2343 c 4′-F dm Gen. A, D 461.2 344 f H dl Gen. A, D 439.3

TABLE 12

R₅ Groups aa

bb

cc

Chiral Separation LCMS SFC/ MS RT HPLC # of Example # W X Y Z R₃ R₁₀ R₁₄Int. i Int. iii Procedures [M + H] (min.) cond. iso. 350 NMe N CH N^(i)Bu d bb gc di Gen. A, D 492.3 ^(a) 1 351 NMe N CH N Et d aa * daGen. A, D 462.3 ^(a) not separated 2 352 NMe N CH N ^(i)Bu d aa gc daGen. A, D 490.2 ^(a) 1 353 N^(i)Pr C NH N Me d cc ** dm Int. fk, Gen. D514.2 ^(a) not separated 2 354 NMe N CH CH CH₂OMe d cc gf dm Gen. A, D515.2 ^(a) 1 355 O N C^(i)Bu N Me d aa *** da Gen. A, U 491.2 ^(b) 2.52A 1 356 O N C^(i)Bu N Me d aa *** da Gen. A, U 491.2 ^(b) 3.51 A 1 *1-(1-meth-1H-1,2,4-triazol-5-yl)-1-propanamine **α-methyl-4-(1-methylethyl)-4H-1,2,4-triazole-3-methanamine ***α-methyl-3-(1-methylethyl)-1,2,4-Oxadiazole-5-methanamine

Biology Protocols

1. Electrophysiology

Kv1.x currents were measured in K_(V)1.3/CHO or Kv1.5/CHO cells using aplanar electrode version (Nanion Technologies GMBH) of the patch-clamptechnique. Whole-cell Kv1.x current transients were evoked by 500 msdepolarising voltage pulses to +40 mV from a holding potential of −80 mVapplied at 10 s intervals for Kv1.5 and at 30 s intervals for K_(V)1.3to allow adequate time for recovery from inactivation. Cells werecontinuously bathed in a buffered saline solution containing (mM): 160NaCl, 4.5 KCl, 2 CaCl₂, 1 MgCl₂, 5 glucose, 10 HEPES, pH 7.4, 290-310mOsm·Kg⁻¹. The internal (pipette) solution contained (mM): 10 NaCl, 70KF, 75 KCl, 2 MgCl₂, 10 HEPES, 10 EGTA, pH 7.2, 290-310 mOsm·Kg⁻¹.Series resistance compensation (60-80%) was applied to cells in whichthe peak current amplitude exceeded 2 nA.

Compound Preparation and Potency Assessment

Compounds were initially dissolved in DMSO to 10 mM. After furtherdilution in DMSO, compounds were finally diluted in bath solution 1/200(to give a final DMSO concentration of 0.5%) and applied directly to therecording chamber. Compounds were added at increasing concentrationsallowing ample time for steady state block to be achieved between eachconcentration. Each compound was tested at 5-6 different concentrationson 2-3 cells. Compound IC₅₀ values were determined by fitting theaverage normalised reduction of either the current integral or thesteady state current amplitude at the end of the 500 ms depolarisingpulse obtained at each compound concentration to the Hill equation. TheIC₅₀ data reported herein is based on the steady state calculation. 2.Effector Memory T Cell Proliferation Assay with Cytokine Read Out

Inhibition of Proliferation

Inhibition of T_(EM) function in vitro was based on methods published by(Hu et al., 2007, J. Immunol., 179, 4563-4570; Wulff et al., 2003, J.Clin. Invest., 111, 1703-1713; Beeton et al., 2005, Mol. Pharmacol., 67,1369-1381). Peripheral blood mononuclear cells were purified from humanwhole blood preparations using Ficoll density centrifugation. T_(EM)cells were obtained by enrichment of the CD45RA-CCR7-population usingmonoclonal antibodies, labelled magnetic beads and magnetic separation(Miltenyi Biotec). Enriched T_(EM) cells were incubated at aconcentration of 2×10⁵ cells per well in 96-well plates in RPMI mediumsupplemented with 5% human serum, glutamine (Gibco) andpenicillin/streptomycin (Gibco). Once plated, cells were incubated withcompound at varying concentrations for 2 hours at 37° C. before beingstimulated. Compound dilutions were made up in T cell medium+DMSO (tokeep the concentration of DMSO constant within the dilutions) and 75μl/well were added. After two hours, 150 μl of well contents weretransferred to another 96 well plate coated with anti-human CD3 antibody(2 μg/ml overnight and then extensively washed with PBS). 72 hours latertritiated thymidine was added and proliferation of T_(EM) cells measuredby scintillation counting of thymidine incorporation. All incubationstook place in an incubator at 37° C. and 5% CO₂.

Inhibition of Human Interferon Gamma (IFN-γ) and IL-17 Secretion

Peripheral blood mononuclear cells were purified from human whole bloodpreparations using Ficoll density centrifugation. T_(EM) cells wereobtained by enrichment of the CD45RA-CCR7-population using monoclonalantibodies, labelled magnetic beads and magnetic separation (MiltenyiBiotec). Enriched T_(EM) cells were incubated at a concentration of2×10⁵ cells per well in 96-well plates in RPMI medium supplemented with5% human serum, glutamine (Gibco) and penicillin/streptomycin (Gibco).Once plated, cells were incubated with compound dilutions for 2 hours at37° C. before being stimulated. Compound dilutions were made up in Tcell medium+DMSO (to keep the concentration of DMSO constant within thedilutions) and 75 μl/well were added. After two hours, 150 μl of wellcontents were transferred to another 96 well plate coated withanti-human CD3 antibody (2 μg/ml overnight and then extensively washedwith PBS). 72 hours later supernatant was removed and analysed forpresence of human IFNγ or IL-17 using an ELISA kit (R&D Systems) and aFluostar optical density reader (450 nm wavelength filter). Allincubations took place in an incubator at 37° C. and 5% CO₂.

In Vitro Inhibition of Proliferation and Cytokine Secretion byAntigen-Specific Rat T Cells

Lewis rats were immunised subcutaneously with 200 μl OVA protein (Sigma)emulsion in CFA (DIFCO). 7 days later rats were challenged with OVAsolution intradermally into the middle of the right ear. 24 hours laterthe rats were killed and inguinal lymph nodes removed. Followinghomogenisation (gentleMACS Dissociator (MACS Miltenyi Biotec)) andpassage through a filter, cell suspensions were prepared in RPMI(supplemented with 10% FBS (heat-inactivated, Invitrogen) 1% Pen-Strep(Invitrogen), 1% Hepes 1M (Invitrogen), 1% Glutamax (Invitrogen), 1% MEM(SIGMA), 2.5 μM B-mercaptoethanol (Invitrogen), 1 μM sodium pyruvate(Invitrogen) and plated in 96 well plates at a concentration of 5×10⁵cells per well. Cells were left either unstimulated or stimulated withCon A (Sigma) in the presence of compound at varying concentrations andincubated at 37° C., 5% CO₂ for 48 hours. After this time 10 μltritiated thymidine (1 μCi per well) was added to cell proliferationplates and incubated overnight for a further 16 hours at 37° C. and 5%CO2. Plates were frozen (−20° C.) until further use. At a convenienttime, cells were harvested on filters (Filtermat A Perkin Elmer) andtritiated thymidine incorporation was measured using a Microbetacounter.

Duplicate cultures were set up under the same stimulation conditions formeasurement of IFN-γ and IL-17 production. After 72 hours incubation,supernatants were removed and stored at −80° C. until cytokine analysis(IL17A & IFNg, custom Rat 2 Plex Cytokine Panel, IL17-A & IFNgamma, KitLEGENDplex, or Kit Milliplex, MerckMillipore).

Results According to Method D1:

Example IC₅₀ (Kv1.3 ephys steady state, nM) 1 <50 2 50-200 5 <50 8 <50 950-200 10 50-200 13 50-200 14 <50 21 50-200 24 50-200 39 50-200 4050-200 41 50-200 44 200-1000 45 200-1000 46 50-200 47 50-200 51 50-20052 200-1000 53 50-200 54 200-1000 55 200-1000 57 200-1000 61 50-200 62200-1000 63 1000-2000  65 >1000  66 50-200 67 200-1000 74 <50 76 <50 78200-1000 80 200-1000 87 200-1000 88 50-200 89 <50 91 200-1000 92200-1000 93 50-200 94 50-200 95 <50 96 50-200 97 <50 98 50-200 99 <50100 50-200 101 200-1000 110 <50 111 50-200 112 50-200 113 200-1000 11450-200 115 50-200 116 200-1000 117 50-200 118 1000-2000  119 50-200 120200-1000 121 50-200 122 50-200 123 200-1000 124 200-1000 125 1000-2000 126 200-1000 127 50-200 128 50-200 129 50-200 130 200-1000 1401000-2000  141 200-1000 142 200-1000 143 200-1000 144 200-1000 145200-1000 146 200-1000 147 200-1000 148 200-1000 150 200-1000 151200-1000 152 200-1000 153 1000-2000  154 200-1000 155 200-1000 15650-200 157 200-1000 158 200-1000 159 200-1000 160 200-1000 161 200-1000162 200-1000 163 200-1000 170 200-1000 171 200-1000 172 50-200 17350-200 174 50-200 175 200-1000 176 50-200 180 50-200 182 50-200 183200-1000 184 200-1000 186 200-1000 187 200-1000 188 50-200 189 200-1000190 <50 191 50-200 192 200-1000 193 50-200 196 50-200 197 50-200 21250-200 214 50-200 215 50-200 216 50-200 217 50-200 218 50-200 219 50-200220 50-200 221 200-1000 222 50-200 223 50-200 224 200-1000 225 200-1000226 200-1000 227 50-200 228 50-200 229 50-200 230 50-200 231 50-200 23250-200 233 50-200 234 200-1000 235 200-1000 236 50-200 237 50-200 23850-200 239 200-1000 240 200-1000 241 200-1000 242 50-200 243 50-200 244200-1000 245 200-1000 246 200-1000 247 50-200 248 200-1000 249 50-200250 200-1000 251 200-1000 252 50-200 253 <50 254 50-200 255 <50 26050-200 261 200-1000 262 <50 263 50-200 264 <50 265 50-200 269 50-200 27050-200 271 200-1000 272 50-200 280 200-1000 281 200-1000 282 50-200 28350-200 284 200-1000 287 200-1000 288 1000-2000  290 50-200 291 50-200292 200-1000 293 50-200 294 50-200 295 50-200 296 <50 297 200-1000 298200-1000 299 50-200 300 50-200 301 50-200 302 50-200 303 50-200 30450-200 305 50-200 306 200-1000 307 50-200 308 50-200 309 50-200 310200-1000 311 200-1000 312 50-200 313 50-200 314 200-1000 315 200-1000316 200-1000 317 200-1000 318 50-200 319 50-200 320 <50 321 200-100  32250-200 323 200-1000 324 50-200 327 1000-2000  328 200-1000 329 50-200330 50-200 331 50-200 332 50-200 333 200-1000 340 200-1000 341 200-1000342 200-1000 343 200-1000 344 200-1000 350 200-1000 351 200-1000 35250-200 354 200-1000 355 50-200 356 50-200

1-113. (canceled)
 114. A method of treating a condition selected fromautoimmune disorders, immune-mediated disorders, inflammatory disorders,or other disorders, or conditions which benefit clinically fromimmunosuppressants, including multiple sclerosis, type-1 diabetesmellitus, type-2 diabetes mellitus, rheumatoid arthritis, systemic lupuserythematosus, psoriasis, contact dermatitis, obesity, graft-versus hostdisease, transplant rejection, and delayed type hypersensitivity,including the step of administering an effective amount of a compoundaccording to Formula (I):

wherein G¹ denotes a single bond, G² denotes a CO group, X is selectedfrom a single bond, an alkylene group having 1 to 6 carbon atomsoptionally substituted with 1 or 2 substituents selected from fluoro orC₁-C₆-alkyl, Y is selected from an alkylene group having 1 to 6 carbonatoms optionally substituted one or two times with C₃-C₈-cycloalkyl orC₁-C₃-alkyl; or a 3-8-membered cycloalkylene group, Q is selected fromO, NH or a single bond, W is selected from SO, SO₂ or a single bond, Uis cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of theabove groups being optionally substituted with 1 to 3 substituentsselected from Hal, NO₂, CN, —SO₂—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, NMe₂,C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a 5-6-memberedheteroaromatic group being optionally substituted by Hal, V is an arylgroup optionally substituted with 1 to 3 substituents selected from Hal,NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkyl or a5-6-membered heteroaromatic group, T denotes phenyl, triazolyl,thiazolyl, oxazolyl, oxadiazolyl, or pyrazolyl, R¹ is Hal, —C₁-C₆-alkyl,O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl, R² and R^(2′)are independently from one another H, Hal, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or R¹ and R² arelinked to form with the ring T to which they are attached a7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, eachof which may be optionally substituted with 1 to 3 Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or—O—C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, or —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a3-8-membered cycloalkyl group, optionally substituted with 1 to 3substituents independently selected from Hal, —C₁-C₆-halo-alkyl, orC₁-C₆-alkyl; or a 3-8-membered heterocyclic group, optionallysubstituted with 1 to 3 substituents independently selected from Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,—SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or—C(O)O—C₁-C₆-alkyl, R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³a 3-8-membered cycloalkyl ring, optionally substituted with Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—O—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl, m is selectedfrom 1, 2, 3 or 4, preferably 1 or 2, Hal is F, Cl, Br, or I, wherein-G²-Y—W together is at least 3 atoms in length, or a pharmaceuticallyacceptable salts thereof, or an enantiomeric mixture of 2 enantiomers inall ratios, and/or as a mixture of diastereoisomers in all ratios. 115.The method according to claim 114 wherein V is a phenyl group optionallysubstituted with 1 to 3 substituents selected from Hal, NO₂, CN,SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkyl or a5-6-membered heteroaromatic group.
 116. The method according to claim114 wherein U is a 5-6-membered cycloalkyl group, a 5-12-memberedheterocyclyl or a 5-6 membered heteroaryl, each of the above groupsbeing optionally substituted with 1 to 3 substituents selected from Hal,NO₂, CN, SO₂, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl,—S—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a 5-6-membered heteroaromaticgroup being optionally substituted by Hal.
 117. The method according toclaim 114 wherein T is phenyl, triazolyl, or oxadiazolyl.
 118. Themethod according to claim 114 wherein R¹ is O—C₁-C₆-alkyl, Hal,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—SO₂—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl, or cyano, inwhich m is
 1. 119. The method according to claim 114 wherein R² andR^(2′) are H or Hal.
 120. The method according to claim 114 wherein R²is H or Hal and R^(2′) is H.
 121. The method according to claim 114wherein R¹ is O—C₁-C₆-alkyl, Hal, —(CH₂)_(m)—O—C₁-C₆-alkyl,—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl,—SO₂-3-8-cycloalkyl, or cyano, in which m is 1, R² is H or Hal andR^(2′) is H.
 122. The method according to claim 114 wherein R¹ and R²are linked to form with the ring T to which they are attached adihydrobenzofuranyl, an indanyl,

 each of these groups being optionally substituted with 1 to 3 Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or—O—C₁-C₆-alkyl.
 123. The method according to claim 114 wherein R⁴ is Hand R³ is C₁-C₆ alkyl, cyclopropyl, or a 3-8-membered heterocyclicgroup.
 124. The method according to claim 114 wherein R⁴ is H and R³ isC₁-C₆ alkyl or cyclopropyl.
 125. The method according to claim 114wherein R⁴ is H and R³ is cyclopropyl.
 126. The method according toclaim 114 wherein R⁴ is H and R³ is ethyl.
 127. The method according toclaim 114 wherein R³ and R⁴ are independently C₁-C₃-alkyl.
 128. Themethod according to claim 127 wherein R³ and R⁴ are both methyl. 129.The method according to claim 114 wherein the compound of formula (I) isrepresented by formula (Ia):

wherein: X is selected from a single bond, an alkylene group having 1 to6 carbon atoms optionally substituted with 1 or 2 substituents selectedfrom fluoro or C₁-C₆-alkyl, Y is selected from an alkylene group having1 to 6 carbon atoms optionally substituted one or two times withC₃-C₈-cycloalkyl or C₁-C₃-alkyl; or a 3-8-membered cycloalkylene group,Q is selected from O, NH or a single bond, V is an aryl group optionallysubstituted with 1 to 3 substituents selected from Hal, NO₂, CN,SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkyl or a5-6-membered heteroaromatic group, U is cycloalkyl, cycloalkenyl,heterocyclyl or heteroaryl, each of the above groups being optionallysubstituted with 1 to 3 substituents selected from Hal, NO₂, CN,—SO₂—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a5-6-membered heteroaromatic group being optionally substituted by Hal, Tdenotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, orpyrazolyl. R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl, R² and R^(2′)are independently from one another H, Hal, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or R¹ and R² arelinked to form with the ring T to which they are attached a7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, eachof which may be optionally substituted with 1 to 3 Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or—O—C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, or —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a3-8-membered cycloalkyl group, optionally substituted with 1 to 3substitutents independently selected from Hal, —C₁-C₆-halo-alkyl, orC₁-C₆-alkyl; or a 3-8-membered heterocyclic group, optionallysubstituted with 1 to 3 substitutents independently selected from Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,—SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or—C(O)O—C₁-C₆-alkyl, R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³a 3-8-membered cycloalkyl ring, optionally substituted with Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—O—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl, and each m isindependently selected from 1, 2, 3, or 4 preferably 1 or 2; or apharmaceutically acceptable salts thereof.
 130. The method according toclaim 114 wherein the compound of formula (I) is represented by formula(Ib)

wherein: X is selected from a single bond, an alkylene group having 1 to6 carbon atoms optionally substituted with 1 or 2 substituents selectedfrom fluoro or C₁-C₆-alkyl, Y is a 3-membered cycloalkylene group. Q isselected from O, NH or a single bond, V is an aryl group optionallysubstituted with 1 to 3 substituents selected from Hal, NO₂, CN,SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkyl or a5-6-membered heteroaromatic group, U is cycloalkyl, cycloalkenyl,heterocyclyl or heteroaryl, each of the above groups being optionallysubstituted with 1 to 3 substituents selected from Hal, NO₂, CN,—SO₂—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a5-6-membered heteroaromatic group being optionally substituted by Hal, Tdenotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, orpyrazolyl, R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl, R² and R^(2′)are independently from one another H, Hal, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or R¹ and R² arelinked to form with the ring T to which they are attached a7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, eachof which may be optionally substituted with 1 to 3 Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or—O—C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, or —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a3-8-membered cycloalkyl group, optionally substituted with 1 to 3substituents independently selected from Hal, —C₁-C₆-halo-alkyl, orC₁-C₆-alkyl; or a 3-8-membered heterocyclic group, optionallysubstituted with 1 to 3 substituents independently selected from Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,—SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or—C(O)O—C₁-C₆-alkyl, R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³a 3-8-membered cycloalkyl ring, optionally substituted with Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—O—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl, and each m isindependently selected from 1, 2, 3 or 4, or a pharmaceuticallyacceptable salts thereof, or an enantiomeric mixture of 2 enantiomers inall ratios, and/or as a mixture of diastereoisomers in all ratios. 131.The method according to claim 114 wherein the compound of formula (I) isrepresented by formula (Ic):

wherein: X is selected from a single bond, an alkylene group having 1 to6 carbon atoms optionally substituted with 1 or 2 substituents selectedfrom fluoro or C₁-C₆-alkyl, Y is an alkylene group having 1 to 6 carbonatoms, Q is selected from O, NH or a single bond, V is an aryl groupoptionally substituted with 1 to 3 substituents selected from Hal, NO₂,CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkyl or a5-6-membered heteroaromatic group, U is cycloalkyl, cycloalkenyl,heterocyclyl or heteroaryl, each of the above groups being optionallysubstituted with 1 to 3 substituents selected from Hal, NO₂, CN,—SO₂—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, NMe₂, C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl,O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a5-6-membered heteroaromatic group being optionally substituted by Hal, Tis a phenyl, triazolyl, thiazolyl, an oxazolyl, an oxadiazolyl, orpyrazolyl group, R¹ is Hal, —C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl, R² and R^(2′)are independently from one another H, Hal, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or R¹ and R² arelinked to form with the ring T to which they are attached a7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, eachof which may be optionally substituted with 1 to 3 Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl, or—O—C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, C₁-C₆-haloalkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, or —(CH₂)_(m)—O—C₁-C₆-haloalkyl; a3-8-membered cycloalkyl group, optionally substituted with 1 to 3substituents independently selected from Hal, —C₁-C₆-halo-alkyl, orC₁-C₆-alkyl; or a 3-8-membered heterocyclic group, optionallysubstituted with 1 to 3 substituents independently selected from Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl,—SO₂—C₁-C₆-halo-alkyl, —O—C₁-C₆-halo-alkyl, —C(O)—C₁-C₆-alkyl, or—C(O)O—C₁-C₆-alkyl, R⁴ denotes H, C₁-C₆-alkyl, or forms together with R³a 3-8-membered cycloalkyl ring, optionally substituted with Hal,—C₁-C₆-halo-alkyl, NO₂, CN, C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,—O—C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl, or —C(O)O—C₁-C₆-alkyl, each m isindependently selected from 1, 2, 3 or 4, or a pharmaceuticallyacceptable salts thereof, or an enantiomeric mixture of 2 enantiomers inall ratios, and/or as a mixture of diastereoisomers in all ratios. 132.The method according to claim 114 wherein the compound of formula (I) isrepresented by formula (II):

Wherein G1 denotes a single bond, G2 denotes a CO group, X is selectedfrom a single bond, an alkylene group having 1 to 6 carbon atomsoptionally substituted with 1 or 2 substituents selected from fluoro orC₁-C₆-alkyl, Y is selected from an alkylene group having 1 to 6 carbonatoms optionally substituted one or two times with C₃-C₅-cycloalkyl orC₁-C₃-alkyl; or a 3-8-membered cycloalkylene group, Q is selected fromO, NH or a single bond, W is selected from SO, SO₂ or a single bond, Uis cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of theabove groups being optionally substituted with 1 to 3 substitutentsselected from Hal, NO₂, CN, —SO₂—C₁-C₆-alkyl, —S—C₁-C₆-alkyl, NMe₂,C₁-C₆-alkyl, —C(O)O—C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, or a 5-6-memberedheteroaromatic group being optionally substituted by Hal, V is an arylgroup optionally substituted with 1 to 3 substitutents selected fromHal, NO₂, CN, SO₂—C₁-C₆ alkyl, NMe₂, C₁-C₆-alkyl, O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, —C₁-C₆-halo-alkyl, O—C₁-C₆-halo-alkyl or a5-6-membered heteroaromatic group, T denotes phenyl, triazolyl,thiazolyl, oxazolyl, oxadiazolyl, or pyrazolyl, R¹ is H, Hal,—C₁-C₆-alkyl, O—C₁-C₆-alkyl, —(CH₂)_(m)—O—C₁-C₆-alkyl,O—C₁-C₆-halo-alkyl, —(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, cyano or —C₁-C₆-halo-alkyl, R² and R^(2′)are independently from one another H, Hal, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—(CH₂)_(m)—O—C₁-C₆-alkyl, O—C₁-C₆-halo-alkyl,—(CH₂)_(m)—O—C₁-C₆-halo-alkyl, —SO₂—C₁-C₆-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-alkyl, —SO₂—C₁-C₆-halo-alkyl,—(CH₂)_(m)—SO₂—C₁-C₆-halo-alkyl, —SO₂-3-8-cycloalkyl,—(CH₂)_(m)—SO₂-3-8-cycloalkyl, —C₁-C₆-halo-alkyl, or R¹ and R² arelinked to form with the ring T to which they are attached a7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, andoptionally substituted with 1 to 3 Hal, —C₁-C₆-halo-alkyl, NO₂, CN, alinear or branched alkyl group having 1 to 6 carbon atoms,—(CH₂)_(m)—O—C₁-C₆-alkyl, or —O—C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, R⁴ isC₁-C₆-alkyl, m is selected from 1, 2, 3 or 4, preferably 1 or 2, Hal isF, Cl, Br, or I, wherein -G²-Y—W together is at least 3 atoms in length,or a pharmaceutically acceptable salts thereof, or an enantiomericmixture of 2 enantiomers in all ratios, and/or as a mixture ofdiastereoisomers in all ratios.
 133. The method according to claim 114for treating a condition selected from Multiple sclerosis, Rheumatoidarthritis, Psoriasis, Type 1 Diabetes, Type II Diabetes, Systemic lupusnephritis, Oncology, Glomerulonephritis, Sjögrens's syndrome, Transplantrejection, Graft versus host disease, Allergic contact dermatitis,Neointimal hyperplasia/restenosis, Periodontal disease, Leprosy, orObesity.